chr11-124923824-G-A

Variant names:

• chr11-124923824-G-A
• rs746134081
• NM_152722.5:c.614C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001411043.1(HEPACAM):​c.614C>T​(p.Thr205Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,856 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HEPACAM NM_001411043.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.90
• Publications: 1 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: 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

ENSG00000254943 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2593573).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001411043.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPACAM	NM_152722.5	MANE Select	c.614C>T	p.Thr205Ile	missense	Exon 3 of 7	NP_689935.2
	HEPACAM	NM_001411043.1		c.614C>T	p.Thr205Ile	missense	Exon 3 of 7	NP_001397972.1
	HEPACAM	NM_001441320.1		c.614C>T	p.Thr205Ile	missense	Exon 3 of 7	NP_001428249.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPACAM	ENST00000298251.5	TSL:1 MANE Select	c.614C>T	p.Thr205Ile	missense	Exon 3 of 7	ENSP00000298251.4
	HEPACAM	ENST00000872129.1		c.614C>T	p.Thr205Ile	missense	Exon 3 of 7	ENSP00000542188.1
	HEPACAM	ENST00000703807.1		c.614C>T	p.Thr205Ile	missense	Exon 3 of 7	ENSP00000515485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Megalencephalic leukoencephalopathy with subcortical cysts 2A;C3151356:Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability;C5779875:Megalencephalic leukoencephalopathy with subcortical cysts 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.098
Sift	Benign	0.037	D
Sift4G	Benign	0.066	T
Polyphen		0.67	P
Vest4		0.30
MutPred		0.62		Loss of ubiquitination at K200 (P = 0.0699)
MVP		0.25
MPC		0.36
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.61
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs746134081; hg19: chr11-124793720;