11-124923851-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_152722.5(HEPACAM):c.587C>A(p.Ser196Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HEPACAM
NM_152722.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 10.0

Publications

3 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

PP5

Variant 11-124923851-G-T is Pathogenic according to our data. Variant chr11-124923851-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 30914.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPACAM	NM_152722.5 link	c.587C>A	p.Ser196Tyr	missense_variant	Exon 3 of 7	ENST00000298251.5	NP_689935.2	Q14CZ8-1
HEPACAM	NM_001411043.1 link	c.587C>A	p.Ser196Tyr	missense_variant	Exon 3 of 7		NP_001397972.1
HEPACAM	NM_001441320.1 link	c.587C>A	p.Ser196Tyr	missense_variant	Exon 3 of 7		NP_001428249.1
LOC107984406	XR_001748429.3 link	n.335-19549G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPACAM	ENST00000298251.5 link	c.587C>A	p.Ser196Tyr	missense_variant	Exon 3 of 7	1	NM_152722.5	ENSP00000298251.4		Q14CZ8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251350

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000459

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 2A

Pathogenic:1

Apr 08, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.40

MutationAssessor

Pathogenic

3.0

PhyloP100

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.54

Sift

Uncertain

0.019

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.98

MutPred

0.52

Loss of disorder (P = 0.022);

MVP

0.69

MPC

1.2

ClinPred

0.98

GERP RS

5.7

Varity_R

0.66

gMVP

0.91

Mutation Taster

=7/93

disease causing (ClinVar)

(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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11-124923851-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over