Genetic Variant HEPACAM2:p.Arg298Cys (chr7-93208700-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039372.4(HEPACAM2):c.892C>T(p.Arg298Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HEPACAM2
NM_001039372.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.10

Variant links:

Genes affected

HEPACAM2 (HGNC:27364): (HEPACAM family member 2) This gene encodes a protein related to the immunoglobulin superfamily that plays a role in mitosis. Knockdown of this gene results in prometaphase arrest, abnormal nuclear morphology and apoptosis. Poly(ADP-ribosylation) of the encoded protein promotes its translocation to centrosomes, which may stimulate centrosome maturation. A chromosomal deletion including this gene may be associated with myeloid leukemia and myelodysplastic syndrome in human patients. [provided by RefSeq, Oct 2016]

HEPACAM2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPACAM2	NM_001039372.4 link	c.892C>T	p.Arg298Cys	missense_variant	Exon 4 of 10	ENST00000394468.7	NP_001034461.1	A8MVW5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEPACAM2	ENST00000394468.7 link	c.892C>T	p.Arg298Cys	missense_variant	Exon 4 of 10	2	NM_001039372.4	ENSP00000377980.2	A8MVW5-1
HEPACAM2	ENST00000440868.5 link	c.856C>T	p.Arg286Cys	missense_variant	Exon 3 of 8	1		ENSP00000389592.1	C9JN07
HEPACAM2	ENST00000341723.8 link	c.856C>T	p.Arg286Cys	missense_variant	Exon 3 of 9	1		ENSP00000340532.4	A8MVW5-2
HEPACAM2	ENST00000453812.2 link	c.961C>T	p.Arg321Cys	missense_variant	Exon 5 of 11	2		ENSP00000390204.2	A8MVW5-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250498

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.892C>T (p.R298C) alteration is located in exon 4 (coding exon 4) of the HEPACAM2 gene. This alteration results from a C to T substitution at nucleotide position 892, causing the arginine (R) at amino acid position 298 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.053

.;.;T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;.;L;.

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Benign

0.069

T;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.44

MutPred

0.58

.;.;Gain of catalytic residue at P297 (P = 0.0193);.;

MVP

0.46

MPC

0.39

ClinPred

0.79

GERP RS

4.3

Varity_R

0.11

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over