11-124923786-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152722.5(HEPACAM):c.652A>G(p.Met218Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,613,966 control chromosomes in the GnomAD database, including 415,256 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M218T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.76 ( 44418 hom., cov: 32)

Exomes 𝑓: 0.71 ( 370838 hom. )

Consequence

HEPACAM
NM_152722.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.220

Publications

30 publications found

Variant links:

Genes affected

HEPACAM (HGNC:26361): (hepatic and glial cell adhesion molecule) The protein encoded by this gene is a single-pass type I membrane protein that localizes to the cytoplasmic side of the cell membrane. The encoded protein acts as a homodimer and is involved in cell motility and cell-matrix interactions. The expression of this gene is downregulated or undetectable in many cancer cell lines, so this may be a tumor suppressor gene. [provided by RefSeq, Jul 2011]

HEPACAM Gene-Disease associations (from GenCC):

megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
megalencephalic leukoencephalopathy with subcortical cysts 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
macrocephaly-autism syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
megalencephalic leukoencephalopathy with subcortical cysts
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HEPACAM links:

ENSG00000254943 (HGNC:):

ENSG00000254943 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1099867E-6).

BP6

Variant 11-124923786-T-C is Benign according to our data. Variant chr11-124923786-T-C is described in ClinVar as Benign. ClinVar VariationId is 262681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HEPACAM	NM_152722.5 link	c.652A>G	p.Met218Val	missense_variant	Exon 3 of 7	ENST00000298251.5	NP_689935.2
HEPACAM	NM_001411043.1 link	c.652A>G	p.Met218Val	missense_variant	Exon 3 of 7		NP_001397972.1
HEPACAM	NM_001441320.1 link	c.652A>G	p.Met218Val	missense_variant	Exon 3 of 7		NP_001428249.1
LOC107984406	XR_001748429.3 link	n.335-19614T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPACAM	ENST00000298251.5 link	c.652A>G	p.Met218Val	missense_variant	Exon 3 of 7	1	NM_152722.5	ENSP00000298251.4

Frequencies

GnomAD3 genomes

AF:

0.759

AC:

115386

AN:

152108

Hom.:

44366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.875

Gnomad AMI

AF:

0.764

Gnomad AMR

AF:

0.674

Gnomad ASJ

AF:

0.638

Gnomad EAS

AF:

0.902

Gnomad SAS

AF:

0.749

Gnomad FIN

AF:

0.778

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.700

Gnomad OTH

AF:

0.746

GnomAD2 exomes

AF:

0.722

AC:

181481

AN:

251320

AF XY:

0.722

show subpopulations

Gnomad AFR exome

AF:

0.881

Gnomad AMR exome

AF:

0.607

Gnomad ASJ exome

AF:

0.639

Gnomad EAS exome

AF:

0.892

Gnomad FIN exome

AF:

0.769

Gnomad NFE exome

AF:

0.700

Gnomad OTH exome

AF:

0.701

GnomAD4 exome

AF:

0.710

AC:

1037907

AN:

1461740

Hom.:

370838

Cov.:

AF XY:

0.711

AC XY:

516897

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.879

AC:

29425

AN:

33476

American (AMR)

AF:

0.614

AC:

27472

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.638

AC:

16677

AN:

26136

East Asian (EAS)

AF:

0.910

AC:

36119

AN:

39700

South Asian (SAS)

AF:

0.744

AC:

64215

AN:

86256

European-Finnish (FIN)

AF:

0.766

AC:

40883

AN:

53406

Middle Eastern (MID)

AF:

0.714

AC:

4118

AN:

5766

European-Non Finnish (NFE)

AF:

0.697

AC:

775366

AN:

1111884

Other (OTH)

AF:

0.722

AC:

43632

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

17187

34374

51561

68748

85935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19714

39428

59142

78856

98570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.759

AC:

115502

AN:

152226

Hom.:

44418

Cov.:

AF XY:

0.763

AC XY:

56781

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.875

AC:

36373

AN:

41562

American (AMR)

AF:

0.674

AC:

10313

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.638

AC:

2215

AN:

3472

East Asian (EAS)

AF:

0.902

AC:

4661

AN:

5168

South Asian (SAS)

AF:

0.750

AC:

3618

AN:

4822

European-Finnish (FIN)

AF:

0.778

AC:

8244

AN:

10592

Middle Eastern (MID)

AF:

0.714

AC:

210

AN:

294

European-Non Finnish (NFE)

AF:

0.700

AC:

47592

AN:

67998

Other (OTH)

AF:

0.749

AC:

1581

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1433

2865

4298

5730

7163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

852

1704

2556

3408

4260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.717

Hom.:

132133

Bravo

AF:

0.755

TwinsUK

AF:

0.717

AC:

2659

ALSPAC

AF:

0.703

AC:

2711

ESP6500AA

AF:

0.878

AC:

3864

ESP6500EA

AF:

0.687

AC:

5911

ExAC

AF:

0.728

AC:

88427

Asia WGS

AF:

0.849

AC:

2954

AN:

3478

EpiCase

AF:

0.699

EpiControl

AF:

0.694

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Megalencephalic leukoencephalopathy with subcortical cysts 2A

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Megalencephalic leukoencephalopathy with subcortical cysts

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.014

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.13

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.47

PhyloP100

0.22

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.24

REVEL

Benign

0.052

Sift

Benign

0.83

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.029

MPC

0.31

ClinPred

0.00073

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.052

gMVP

0.29

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over