11-2377575-G-A

Variant names:

• chr11-2377575-G-A
• NM_004356.4:c.26G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004356.4(CD81):​c.26G>A​(p.Cys9Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C9C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD81 NM_004356.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39
• Publications: 0 publications found

Genes affected

CD81 (HGNC:1701): (CD81 molecule) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This protein appears to promote muscle cell fusion and support myotube maintenance. Also it may be involved in signal transduction. This gene is localized in the tumor-suppressor gene region and thus it is a candidate gene for malignancies. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

CD81-AS1 (HGNC:49384): (CD81 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004356.4. 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
	CD81	NM_004356.4	MANE Select	c.26G>A	p.Cys9Tyr	missense	Exon 1 of 8	NP_004347.1	P60033
	CD81	NM_001425135.1		c.26G>A	p.Cys9Tyr	missense	Exon 1 of 8	NP_001412064.1
	CD81	NM_001425137.1		c.26G>A	p.Cys9Tyr	missense	Exon 1 of 8	NP_001412066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD81	ENST00000263645.10	TSL:1 MANE Select	c.26G>A	p.Cys9Tyr	missense	Exon 1 of 8	ENSP00000263645.5	P60033
	CD81-AS1	ENST00000427151.1	TSL:1	n.404+11C>T		intron	N/A
	CD81	ENST00000905044.1		c.26G>A	p.Cys9Tyr	missense	Exon 4 of 11	ENSP00000575103.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.26e-7 AC: 1 AN: 1376708 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 682872

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28624

American (AMR) AF: 0.00 AC: 0 AN: 37490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23442

East Asian (EAS) AF: 0.00 AC: 0 AN: 32714

South Asian (SAS) AF: 0.00 AC: 0 AN: 79372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066270

Other (OTH) AF: 0.00 AC: 0 AN: 55556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.90		Loss of methylation at K8 (P = 0.0205)
MVP		0.86
MPC		2.1
ClinPred		1.0	D
GERP RS		2.5
PromoterAI		0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.76
gMVP		0.62
Mutation Taster		=18/82	disease causing

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

hg19: chr11-2398805; COSMIC: COSV99719152; COSMIC: COSV99719152;