12-10433940-G-C

Variant names:

• chr12-10433940-G-C
• rs373440622
• NM_002260.4:c.334C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_002260.4(KLRC2):​c.334C>G​(p.Arg112Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,402,944 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (1 hom., cov: 27)
  • Exomes 𝑓: 0.0000036 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLRC2 NM_002260.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 2 publications found

Genes affected

KLRC2 (HGNC:6375): (killer cell lectin like receptor C2) Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. The group, designated KLRC (NKG2) are expressed primarily in natural killer (NK) cells and encodes a family of transmembrane proteins characterized by a type II membrane orientation (extracellular C terminus) and the presence of a C-type lectin domain. The KLRC (NKG2) gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. KLRC2 alternative splice variants have been described but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000255641 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLRC2	NM_002260.4	MANE Select	c.334C>G	p.Arg112Gly	missense splice_region	Exon 4 of 6	NP_002251.2	P26717

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLRC2	ENST00000381902.7	TSL:1 MANE Select	c.334C>G	p.Arg112Gly	missense splice_region	Exon 4 of 6	ENSP00000371327.2	P26717
	ENSG00000255641	ENST00000539033.1	TSL:1	c.331+546C>G		intron	N/A	ENSP00000437563.1	F5H6K3
	KLRC2	ENST00000381901.5	TSL:5	c.334C>G	p.Arg112Gly	missense splice_region	Exon 4 of 6	ENSP00000371326.1	J3KPJ4

Frequencies

GnomAD3 genomes AF: 0.0000141 AC: 2 AN: 141944 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000138

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

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1402944 Hom.: 2 Cov.: 30 AF XY: 0.00000716 AC XY: 5 AN XY: 698258

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000650 AC: 2 AN: 30752

American (AMR) AF: 0.0000463 AC: 2 AN: 43154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24698

East Asian (EAS) AF: 0.00 AC: 0 AN: 37386

South Asian (SAS) AF: 0.00 AC: 0 AN: 83390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069184

Other (OTH) AF: 0.0000174 AC: 1 AN: 57630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000141 AC: 2 AN: 141944 Hom.: 1 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 69154

African (AFR) AF: 0.00 AC: 0 AN: 37188

American (AMR) AF: 0.000138 AC: 2 AN: 14530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3292

East Asian (EAS) AF: 0.00 AC: 0 AN: 4740

South Asian (SAS) AF: 0.00 AC: 0 AN: 4568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64776

Other (OTH) AF: 0.00 AC: 0 AN: 1940

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.42
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.011
Sift	Benign	0.29	T
Sift4G	Benign	0.27	T
Vest4		0.19
MutPred		0.47		Gain of catalytic residue at H116 (P = 0)
MVP		0.12
MPC		0.40
ClinPred		0.20	T
GERP RS		-3.1
PromoterAI		-0.098	Neutral
gMVP		0.21
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs373440622; hg19: chr12-10586539;