Genetic Variant HEPACAM:p.Met218Leu (chr11-124923786-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152722.5(HEPACAM):c.652A>T(p.Met218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M218V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

HEPACAM
NM_152722.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06283319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HEPACAM	NM_152722.5 link	c.652A>T	p.Met218Leu	missense_variant	Exon 3 of 7	ENST00000298251.5	NP_689935.2
HEPACAM	NM_001411043.1 link	c.652A>T	p.Met218Leu	missense_variant	Exon 3 of 7		NP_001397972.1
HEPACAM	NM_001441320.1 link	c.652A>T	p.Met218Leu	missense_variant	Exon 3 of 7		NP_001428249.1
LOC107984406	XR_001748429.3 link	n.335-19614T>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.652A>T	p.Met218Leu	missense_variant	Exon 3 of 7	1	NM_152722.5	ENSP00000298251.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

9.4

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.013

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.36

M_CAP

Benign

0.0054

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.49

PhyloP100

0.22

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.11

REVEL

Benign

0.014

Sift

Benign

0.76

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MutPred

0.33

Loss of phosphorylation at Y215 (P = 0.0909);

MVP

0.10

MPC

0.29

ClinPred

0.083

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.32

Mutation Taster

=98/2

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over