rs570071609

Variant names:

• chr11-124923846-C-T
• rs570071609
• NM_152722.5:c.592G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152722.5(HEPACAM):​c.592G>A​(p.Asp198Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HEPACAM NM_152722.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 5.05
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24887323).

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.592G>A	p.Asp198Asn	missense	Exon 3 of 7	NP_689935.2	Q14CZ8-1
	HEPACAM	NM_001411043.1		c.592G>A	p.Asp198Asn	missense	Exon 3 of 7	NP_001397972.1	A0A994J4I1
	HEPACAM	NM_001441320.1		c.592G>A	p.Asp198Asn	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.592G>A	p.Asp198Asn	missense	Exon 3 of 7	ENSP00000298251.4	Q14CZ8-1
	HEPACAM	ENST00000872129.1		c.592G>A	p.Asp198Asn	missense	Exon 3 of 7	ENSP00000542188.1
	HEPACAM	ENST00000703807.1		c.592G>A	p.Asp198Asn	missense	Exon 3 of 7	ENSP00000515485.1	A0A994J4I1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251358 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000752 AC: 11 AN: 1461840 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74444

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Benign	0.20	T
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.36		Gain of ubiquitination at K200 (P = 0.0975)
MVP		0.62
MPC		1.0
ClinPred		0.90	D
GERP RS		3.8
Varity_R		0.27
gMVP		0.68
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs570071609; hg19: chr11-124793742;