rs10790715

Variant names:

• chr11-124923786-T-C
• rs10790715
• NM_152722.5:c.652A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-124923786-T-C
• chr11-124923786-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.220
• Publications: 30 publications found

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: ClinGen, Ambry Genetics, 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

ENSG00000254943 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152722.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPACAM	NM_152722.5	MANE Select	c.652A>G	p.Met218Val	missense	Exon 3 of 7	NP_689935.2	Q14CZ8-1
	HEPACAM	NM_001411043.1		c.652A>G	p.Met218Val	missense	Exon 3 of 7	NP_001397972.1	A0A994J4I1
	HEPACAM	NM_001441320.1		c.652A>G	p.Met218Val	missense	Exon 3 of 7	NP_001428249.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPACAM	ENST00000298251.5	TSL:1 MANE Select	c.652A>G	p.Met218Val	missense	Exon 3 of 7	ENSP00000298251.4	Q14CZ8-1
	HEPACAM	ENST00000872129.1		c.652A>G	p.Met218Val	missense	Exon 3 of 7	ENSP00000542188.1
	HEPACAM	ENST00000703807.1		c.652A>G	p.Met218Val	missense	Exon 3 of 7	ENSP00000515485.1	A0A994J4I1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115386 AN: 152108 Hom.: 44366 Cov.: 32

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

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.: 60 AF XY: 0.711 AC XY: 516897 AN XY: 727170

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

GnomAD4 genome AF: 0.759 AC: 115502 AN: 152226 Hom.: 44418 Cov.: 32 AF XY: 0.763 AC XY: 56781 AN XY: 74422

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

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Megalencephalic leukoencephalopathy with subcortical cysts (1)
-	-	1	Megalencephalic leukoencephalopathy with subcortical cysts 2A (1)
-	-	1	Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DANN	Benign	0.82
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.47	N
PhyloP100		0.22
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.052
Sift	Benign	0.83	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.31
ClinPred		0.00073	T
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)

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

Other links and lift over

dbSNP: rs10790715; hg19: chr11-124793682; COSMIC: COSV99035985; COSMIC: COSV99035985;