rs387907052

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_152722.5(HEPACAM):c.292C>T(p.Arg98Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HEPACAM
NM_152722.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 7.99

Publications

6 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: Pathogenic. The variant received 10 ACMG points.

PM1

In a domain Ig-like V-type (size 108) in uniprot entity HECAM_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_152722.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 11-124924863-G-A is Pathogenic according to our data. Variant chr11-124924863-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30918.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.292C>T	p.Arg98Cys	missense_variant	Exon 2 of 7	ENST00000298251.5	NP_689935.2	Q14CZ8-1
HEPACAM	NM_001411043.1 link	c.292C>T	p.Arg98Cys	missense_variant	Exon 2 of 7		NP_001397972.1
HEPACAM	NM_001441320.1 link	c.292C>T	p.Arg98Cys	missense_variant	Exon 2 of 7		NP_001428249.1
LOC107984406	XR_001748429.3 link	n.335-18537G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPACAM	ENST00000298251.5 link	c.292C>T	p.Arg98Cys	missense_variant	Exon 2 of 7	1	NM_152722.5	ENSP00000298251.4		Q14CZ8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

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:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000550

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 2A

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 08, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Aug 17, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: abnormal protein trafficking and reduced ability to homo-oligermize and interact with MLC1 (PMID: 21624973); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25044933, 22405205, 31960914, 26986070, 26659599, 21624973, 21419380) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.4

PhyloP100

8.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.88

Gain of catalytic residue at R96 (P = 0.1362);

MVP

0.71

MPC

1.2

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.96

Mutation Taster

=9/91

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over