12-10408225-T-G

Variant names:

• chr12-10408225-T-G
• rs2617169
• NM_013431.2:c.340+104A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013431.2(KLRC4):​c.340+104A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 555,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: KLRC4 NM_013431.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385
• Publications: 8 publications found

Genes affected

KLRC4 (HGNC:6377): (killer cell lectin like receptor C4) 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. This gene is a member of the NKG2 group of genes that are expressed primarily in natural killer (NK) cells. These family members encode transmembrane proteins that are characterized by a type II membrane orientation (have an extracellular C-terminus) and the presence of a C-type lectin domain. This family member is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed in NK cells. Read-through transcription exists between this gene and the downstream KLRK1 (killer cell lectin-like receptor subfamily K, member 1) family member. [provided by RefSeq, Dec 2010]

KLRC4-KLRK1 (HGNC:48357): (KLRC4-KLRK1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring KLRC4 (killer cell lectin-like receptor subfamily C, member 4) and KLRK1 (killer cell lectin-like receptor subfamily K, member 1) genes on chromosome 12. The read-through transcript includes an alternate 5' exon and lacks a significant portion of the KLRC4 coding sequence, including the start codon, and it thus encodes the KLRK1 protein. [provided by RefSeq, Dec 2010]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC4	NM_013431.2	c.340+104A>C		intron_variant	Intron 3 of 3	ENST00000309384.3	NP_038459.1
KLRC4-KLRK1	NM_001199805.1	c.-335+104A>C		intron_variant	Intron 3 of 12		NP_001186734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLRC4	ENST00000309384.3	c.340+104A>C		intron_variant	Intron 3 of 3	1	NM_013431.2	ENSP00000310216.1
KLRC4-KLRK1	ENST00000539300.5	n.313+104A>C		intron_variant	Intron 3 of 12	2		ENSP00000455951.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000900 AC: 5 AN: 555826 Hom.: 0 AF XY: 0.00000999 AC XY: 3 AN XY: 300250

African (AFR) AF: 0.00 AC: 0 AN: 12766

American (AMR) AF: 0.0000854 AC: 2 AN: 23428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17596

East Asian (EAS) AF: 0.00 AC: 0 AN: 29802

South Asian (SAS) AF: 0.00 AC: 0 AN: 54772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3570

European-Non Finnish (NFE) AF: 0.00000592 AC: 2 AN: 337956

Other (OTH) AF: 0.0000341 AC: 1 AN: 29362

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 2453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.23
PhyloP100		-0.39

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: rs2617169; hg19: chr12-10560824;