18-69864406-T-C

Position:

• chr18-69864406-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001303618.2(CD226):​c.919A>G​(p.Ser307Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,611,980 control chromosomes in the GnomAD database, including 217,445 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (17901 hom., cov: 32)
  • Exomes 𝑓: 0.52 (199544 hom.)
• Consequence: CD226 NM_001303618.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490

Genes affected

CD226 (HGNC:16961): (CD226 molecule) This gene encodes a glycoprotein expressed on the surface of NK cells, platelets, monocytes and a subset of T cells. It is a member of the Ig-superfamily containing 2 Ig-like domains of the V-set. The protein mediates cellular adhesion of platelets and megakaryocytic cells to vascular endothelial cells. The protein also plays a role in megakaryocytic cell maturation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.352006E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD226	NM_001303618.2	c.919A>G	p.Ser307Gly	missense_variant	6/6	ENST00000582621.6	NP_001290547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD226	ENST00000582621.6	c.919A>G	p.Ser307Gly	missense_variant	6/6	1	NM_001303618.2	ENSP00000461947.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71731 AN: 151884 Hom.: 17903 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.469

GnomAD3 exomes AF: 0.518 AC: 130190 AN: 251140 Hom.: 34505 AF XY: 0.517 AC XY: 70218 AN XY: 135744

Gnomad AFR exome AF: 0.297

Gnomad AMR exome AF: 0.564

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.555

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.521 AC: 760027 AN: 1459980 Hom.: 199544 Cov.: 34 AF XY: 0.519 AC XY: 376914 AN XY: 726396

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.557

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.552

Gnomad4 NFE exome AF: 0.526

Gnomad4 OTH exome AF: 0.512

GnomAD4 genome AF: 0.472 AC: 71746 AN: 152000 Hom.: 17901 Cov.: 32 AF XY: 0.478 AC XY: 35467 AN XY: 74268

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.491

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.527

Gnomad4 OTH AF: 0.468

Alfa AF: 0.510 Hom.: 50469

Bravo AF: 0.459

TwinsUK AF: 0.523 AC: 1939

ALSPAC AF: 0.533 AC: 2053

ESP6500AA AF: 0.318 AC: 1403

ESP6500EA AF: 0.521 AC: 4477

ExAC AF: 0.510 AC: 61954

Asia WGS AF: 0.544 AC: 1890 AN: 3478

EpiCase AF: 0.501

EpiControl AF: 0.499

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.0
DANN	Benign	0.25
DEOGEN2	Benign	0.094	T;T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.32	.;.;T;T
MetaRNN	Benign	0.000054	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;.;.;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.97	N;.;.;.
REVEL	Benign	0.0080
Sift	Benign	0.56	T;.;.;.
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.0010	B;.;.;B
Vest4		0.089
MPC		0.17
ClinPred		0.012	T
GERP RS		0.23
Varity_R		0.035
gMVP		0.17

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: rs763361; hg19: chr18-67531642; COSMIC: COSV54614477;