11-61008834-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006725.5(CD6):c.770C>T(p.Ala257Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,545,390 control chromosomes in the GnomAD database, including 258,994 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. A257A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.58 (25911 hom., cov: 34)
  • Exomes 𝑓: 0.57 (233083 hom.)
• Consequence: CD6 NM_006725.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.50

Genes affected

CD6 (HGNC:1691): (CD6 molecule) This gene encodes a protein found on the outer membrane of T-lymphocytes as well as some other immune cells. The encoded protein contains three scavenger receptor cysteine-rich (SRCR) domains and a binding site for an activated leukocyte cell adhesion molecule. The gene product is important for continuation of T cell activation. This gene may be associated with susceptibility to multiple sclerosis (PMID: 19525953, 21849685). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1915762E-6).
• BP6: Variant 11-61008834-C-T is Benign according to our data. Variant chr11-61008834-C-T is described in ClinVar as [Benign]. Clinvar id is 3059536.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD6	NM_006725.5	c.770C>T	p.Ala257Val	missense_variant	4/13	ENST00000313421.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD6	ENST00000313421.11	c.770C>T	p.Ala257Val	missense_variant	4/13	1	NM_006725.5	P2

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87928 AN: 152034 Hom.: 25897 Cov.: 34

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.633

GnomAD3 exomes AF: 0.535 AC: 103323 AN: 193210 Hom.: 28403 AF XY: 0.541 AC XY: 56298 AN XY: 104034

Gnomad AFR exome AF: 0.641

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.448

Gnomad SAS exome AF: 0.467

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.575 AC: 800477 AN: 1393238 Hom.: 233083 Cov.: 46 AF XY: 0.574 AC XY: 392418 AN XY: 683970

Gnomad4 AFR exome AF: 0.639

Gnomad4 AMR exome AF: 0.407

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.442

Gnomad4 NFE exome AF: 0.593

Gnomad4 OTH exome AF: 0.579

GnomAD4 genome AF: 0.578 AC: 87977 AN: 152152 Hom.: 25911 Cov.: 34 AF XY: 0.568 AC XY: 42229 AN XY: 74376

Gnomad4 AFR AF: 0.636

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.722

Gnomad4 EAS AF: 0.429

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.635

Alfa AF: 0.599 Hom.: 9159

Bravo AF: 0.592

TwinsUK AF: 0.600 AC: 2224

ALSPAC AF: 0.595 AC: 2292

ESP6500AA AF: 0.549 AC: 2410

ESP6500EA AF: 0.548 AC: 4699

ExAC AF: 0.529 AC: 62295

Asia WGS AF: 0.468 AC: 1628 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CD6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.033
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Benign	0.76
DEOGEN2	Benign	0.016	T;T;.;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.50	T;T;T;T;T
MetaRNN	Benign	0.0000022	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.5	N;.;.;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	3.4	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;.;B;B;B
Vest4		0.083
MPC		0.96
ClinPred		0.00047	T
GERP RS		3.3
Varity_R		0.042
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs2074225; hg19: chr11-60776306; COSMIC: COSV57838880; COSMIC: COSV57838880;