NM_002260.4:c.56G>C

Variant names:

• chr12-10435931-C-G
• rs75545535
• NM_002260.4:c.56G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002260.4(KLRC2):​c.56G>C​(p.Arg19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (2 hom., cov: 30)
  • Exomes 𝑓: 0.37 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLRC2 NM_002260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.132
• Publications: 28 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020274222).
• BP6: Variant 12-10435931-C-G is Benign according to our data. Variant chr12-10435931-C-G is described in ClinVar as Benign. ClinVar VariationId is 769386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.56G>C	p.Arg19Pro	missense	Exon 1 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.56G>C	p.Arg19Pro	missense	Exon 1 of 6	ENSP00000371327.2	P26717
	ENSG00000255641	ENST00000539033.1	TSL:1	c.56G>C	p.Arg19Pro	missense	Exon 1 of 7	ENSP00000437563.1	F5H6K3
	KLRC2	ENST00000381901.5	TSL:5	c.56G>C	p.Arg19Pro	missense	Exon 1 of 6	ENSP00000371326.1	J3KPJ4

Frequencies

GnomAD3 genomes AF: 0.225 AC: 20211 AN: 89826 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.0772

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.348 AC: 64580 AN: 185462 AF XY: 0.354

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.285

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.353

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.367 AC: 399928 AN: 1089756 Hom.: 8 Cov.: 144 AF XY: 0.361 AC XY: 194153 AN XY: 537798

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

African (AFR) AF: 0.111 AC: 3016 AN: 27072

American (AMR) AF: 0.257 AC: 7126 AN: 27678

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 4059 AN: 16108

East Asian (EAS) AF: 0.209 AC: 4650 AN: 22302

South Asian (SAS) AF: 0.192 AC: 11242 AN: 58442

European-Finnish (FIN) AF: 0.298 AC: 9592 AN: 32196

Middle Eastern (MID) AF: 0.319 AC: 1279 AN: 4014

European-Non Finnish (NFE) AF: 0.402 AC: 345843 AN: 860392

Other (OTH) AF: 0.316 AC: 13121 AN: 41552

⚠️ 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: InbreedingCoeff AF: 0.225 AC: 20215 AN: 89934 Hom.: 2 Cov.: 30 AF XY: 0.224 AC XY: 9903 AN XY: 44180

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

African (AFR) AF: 0.0770 AC: 2237 AN: 29050

American (AMR) AF: 0.249 AC: 2071 AN: 8302

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 520 AN: 1962

East Asian (EAS) AF: 0.210 AC: 585 AN: 2784

South Asian (SAS) AF: 0.177 AC: 493 AN: 2784

European-Finnish (FIN) AF: 0.274 AC: 1530 AN: 5582

Middle Eastern (MID) AF: 0.134 AC: 23 AN: 172

European-Non Finnish (NFE) AF: 0.327 AC: 12307 AN: 37614

Other (OTH) AF: 0.243 AC: 295 AN: 1214

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.209 Hom.: 1

ExAC AF: 0.411 AC: 49916

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.13
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.019
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0070	D
Vest4		0.085
MPC		1.6
ClinPred		0.078	T
GERP RS		-0.058
PromoterAI		0.0033	Neutral
gMVP		0.14
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs75545535; hg19: chr12-10588530; COSMIC: COSV67899313; COSMIC: COSV67899313;