chr12-55726791-A-G

Position:

chr12-55726791-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001780.6(CD63):c.335T>C(p.Met112Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,208 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CD63
NM_001780.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.84

Variant links:

Genes affected

CD63 (HGNC:1692): (CD63 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. The encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak syndrome. Also this gene has been associated with tumor progression. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Apr 2012]

CD63 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019072324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD63	NM_001780.6 linkuse as main transcript	c.335T>C	p.Met112Thr	missense_variant	5/8	ENST00000257857.9	NP_001771.1	P08962-1A0A024RB05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CD63	ENST00000257857.9 linkuse as main transcript	c.335T>C	p.Met112Thr	missense_variant	5/8	1	NM_001780.6	ENSP00000257857.4	P08962-1
CD63	ENST00000552067.5 linkuse as main transcript	c.56T>C	p.Met19Thr	missense_variant	3/6	5		ENSP00000449684.1	F8VV56
CD63	ENST00000550050.5 linkuse as main transcript	n.*1T>C		non_coding_transcript_exon_variant	5/8	5		ENSP00000449435.1	F8VX62
CD63	ENST00000550050.5 linkuse as main transcript	n.*1T>C		3_prime_UTR_variant	5/8	5		ENSP00000449435.1	F8VX62

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251482

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461024

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000355

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00126

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000378

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.335T>C (p.M112T) alteration is located in exon 5 (coding exon 4) of the CD63 gene. This alteration results from a T to C substitution at nucleotide position 335, causing the methionine (M) at amino acid position 112 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.32

DANN

Benign

0.52

DEOGEN2

Benign

0.13

T;T;T;T;.;T;T;T;.;.;.;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.48

.;T;.;T;.;.;.;.;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.019

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

.;N;.;.;.;N;N;N;.;.;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

0.44

N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.59

T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T;T;T;T;T;T;.;T;T

Polyphen

0.0010

.;B;.;.;.;B;B;B;.;.;.;.;.

Vest4

0.082

MVP

0.62

MPC

0.48

ClinPred

0.0035

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.031

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over