12-10309453-T-G

Position:

• chr12-10309453-T-G

Variant summary

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

The NM_002262.5(KLRD1):​c.73T>G​(p.Ser25Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 1,538,986 control chromosomes in the GnomAD database, including 752,439 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 0.94 (67394 hom., cov: 32)
  • Exomes 𝑓: 0.99 (685045 hom.)
• Consequence: KLRD1 NM_002262.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110

Genes affected

KLRD1 (HGNC:6378): (killer cell lectin like receptor D1) Natural killer (NK) cells are a distinct lineage of lymphocytes that mediate cytotoxic activity and secrete cytokines upon immune stimulation. Several genes of the C-type lectin superfamily, including members of the NKG2 family, are expressed by NK cells and may be involved in the regulation of NK cell function. KLRD1 (CD94) is an antigen preferentially expressed on NK cells and is classified as a type II membrane protein because it has an external C terminus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2017]

KLRD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2583243E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRD1	NM_002262.5	c.73T>G	p.Ser25Ala	missense_variant	2/6	ENST00000336164.9	NP_002253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRD1	ENST00000336164.9	c.73T>G	p.Ser25Ala	missense_variant	2/6	1	NM_002262.5	ENSP00000338130.4

Frequencies

GnomAD3 genomes AF: 0.936 AC: 142344 AN: 152104 Hom.: 67366 Cov.: 32

Gnomad AFR AF: 0.776

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.977

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.951

GnomAD3 exomes AF: 0.983 AC: 247064 AN: 251362 Hom.: 121859 AF XY: 0.988 AC XY: 134207 AN XY: 135846

Gnomad AFR exome AF: 0.767

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.993 AC: 1377499 AN: 1386764 Hom.: 685045 Cov.: 24 AF XY: 0.994 AC XY: 690840 AN XY: 694772

Gnomad4 AFR exome AF: 0.772

Gnomad4 AMR exome AF: 0.987

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.985

GnomAD4 genome AF: 0.936 AC: 142424 AN: 152222 Hom.: 67394 Cov.: 32 AF XY: 0.938 AC XY: 69828 AN XY: 74432

Gnomad4 AFR AF: 0.776

Gnomad4 AMR AF: 0.977

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.952

Alfa AF: 0.990 Hom.: 140726

Bravo AF: 0.926

TwinsUK AF: 0.999 AC: 3705

ALSPAC AF: 0.999 AC: 3852

ESP6500AA AF: 0.771 AC: 3395

ESP6500EA AF: 1.00 AC: 8596

ExAC AF: 0.979 AC: 118848

Asia WGS AF: 0.988 AC: 3438 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.10
DANN	Benign	0.18
DEOGEN2	Benign	0.067	T;T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00033	N
LIST_S2	Benign	0.0055	.;T;.;T
MetaRNN	Benign	0.0000013	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.7	N;N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.3	N;N;N;N
REVEL	Benign	0.034
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.069
MPC		0.12
ClinPred		0.012	T
GERP RS		-3.8
Varity_R		0.036
gMVP		0.12

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: rs10772256; hg19: chr12-10462052;