11-61008698-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006725.5(CD6):c.634C>T(p.Pro212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CD6 NM_006725.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.647

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090125054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD6	NM_006725.5	c.634C>T	p.Pro212Ser	missense_variant	4/13	ENST00000313421.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD6	ENST00000313421.11	c.634C>T	p.Pro212Ser	missense_variant	4/13	1	NM_006725.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455266 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.634C>T (p.P212S) alteration is located in exon 4 (coding exon 4) of the CD6 gene. This alteration results from a C to T substitution at nucleotide position 634, causing the proline (P) at amino acid position 212 to be replaced by a serine (S). 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	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0028	T;T;.;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.26	T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.090	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.64	N;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.73	T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.76	P;.;B;P;B
Vest4		0.064
MutPred		0.50		Gain of catalytic residue at P212 (P = 0.0109);Gain of catalytic residue at P212 (P = 0.0109);Gain of catalytic residue at P212 (P = 0.0109);Gain of catalytic residue at P212 (P = 0.0109);Gain of catalytic residue at P212 (P = 0.0109);
MVP		0.36
MPC		1.7
ClinPred		0.23	T
GERP RS		0.96
Varity_R		0.17
gMVP		0.71

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

Other links and lift over

dbSNP: rs773872697; hg19: chr11-60776170;