rs116102273

Variant names:

• chr11-124921418-T-C
• rs116102273
• NM_152722.5:c.971A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-124921418-T-C
• chr11-124921418-T-G

Variant summary

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

The NM_001411043.1(HEPACAM):​c.1127A>G​(p.Asn376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,270,318 control chromosomes in the GnomAD database, including 1,303 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (293 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1010 hom.)
• Consequence: HEPACAM NM_001411043.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.624
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013171732).
• BP6: Variant 11-124921418-T-C is Benign according to our data. Variant chr11-124921418-T-C is described in ClinVar as Benign. ClinVar VariationId is 262683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0905 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPACAM	NM_152722.5	MANE Select	c.971A>G	p.Asn324Ser	missense	Exon 7 of 7	NP_689935.2
	HEPACAM	NM_001411043.1		c.1127A>G	p.Asn376Ser	missense	Exon 7 of 7	NP_001397972.1
	HEPACAM	NM_001441320.1		c.968A>G	p.Asn323Ser	missense	Exon 7 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.971A>G	p.Asn324Ser	missense	Exon 7 of 7	ENSP00000298251.4
	HEPACAM	ENST00000872129.1		c.1148A>G	p.Asn383Ser	missense	Exon 7 of 7	ENSP00000542188.1
	HEPACAM	ENST00000703807.1		c.1127A>G	p.Asn376Ser	missense	Exon 7 of 7	ENSP00000515485.1

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8345 AN: 151884 Hom.: 291 Cov.: 32

Gnomad AFR AF: 0.0928

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.0683

Gnomad SAS AF: 0.0544

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0584

GnomAD2 exomes AF: 0.0217 AC: 299 AN: 13808 AF XY: 0.0221

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.0464

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.00585

GnomAD4 exome AF: 0.0389 AC: 43470 AN: 1118320 Hom.: 1010 Cov.: 34 AF XY: 0.0387 AC XY: 20604 AN XY: 532976

African (AFR) AF: 0.0898 AC: 2118 AN: 23576

American (AMR) AF: 0.0362 AC: 399 AN: 11018

Ashkenazi Jewish (ASJ) AF: 0.0557 AC: 846 AN: 15178

East Asian (EAS) AF: 0.0668 AC: 1821 AN: 27252

South Asian (SAS) AF: 0.0435 AC: 1181 AN: 27164

European-Finnish (FIN) AF: 0.0208 AC: 479 AN: 23010

Middle Eastern (MID) AF: 0.0495 AC: 151 AN: 3052

European-Non Finnish (NFE) AF: 0.0365 AC: 34382 AN: 942656

Other (OTH) AF: 0.0461 AC: 2093 AN: 45414

GnomAD4 genome AF: 0.0550 AC: 8360 AN: 151998 Hom.: 293 Cov.: 32 AF XY: 0.0553 AC XY: 4108 AN XY: 74304

African (AFR) AF: 0.0930 AC: 3855 AN: 41456

American (AMR) AF: 0.0502 AC: 768 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3464

East Asian (EAS) AF: 0.0681 AC: 350 AN: 5140

South Asian (SAS) AF: 0.0540 AC: 260 AN: 4814

European-Finnish (FIN) AF: 0.0231 AC: 245 AN: 10584

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0371 AC: 2519 AN: 67940

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0423 Hom.: 113

Bravo AF: 0.0578

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.0489 AC: 157

ESP6500EA AF: 0.0226 AC: 154

ExAC AF: 0.0153 AC: 1555

Asia WGS AF: 0.0770 AC: 266 AN: 3478

ClinVar

ClinVar submissions as Germline

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.8
DANN	Benign	0.47
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.62
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.035
Sift	Benign	0.22	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.020
MPC		1.3
ClinPred		0.0083	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.13
Mutation Taster		=100/0	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: rs116102273; hg19: chr11-124791314; COSMIC: COSV53430516; COSMIC: COSV53430516;