7-142942466-G-A

Variant names:

• chr7-142942466-G-A
• rs751310423
• NM_000420.3:c.2005C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000420.3(KEL):​c.2005C>T​(p.Pro669Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P669T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KEL NM_000420.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40
• Publications: 0 publications found

Genes affected

KEL (HGNC:6308): (Kell metallo-endopeptidase (Kell blood group)) This gene encodes a type II transmembrane glycoprotein that is the highly polymorphic Kell blood group antigen. The Kell glycoprotein links via a single disulfide bond to the XK membrane protein that carries the Kx antigen. The encoded protein contains sequence and structural similarity to members of the neprilysin (M13) family of zinc endopeptidases. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18233734).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000420.3. 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
	KEL	NM_000420.3	MANE Select	c.2005C>T	p.Pro669Ser	missense	Exon 18 of 19	NP_000411.1	A0A077QP03

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEL	ENST00000355265.7	TSL:1 MANE Select	c.2005C>T	p.Pro669Ser	missense	Exon 18 of 19	ENSP00000347409.2	P23276
	KEL	ENST00000949853.1		c.1831C>T	p.Pro611Ser	missense	Exon 16 of 17	ENSP00000619912.1
	KEL	ENST00000470850.1	TSL:2	n.305C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455448 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723160

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 43966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 84622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60128

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.24
Sift	Benign	0.23	T
Sift4G	Benign	0.39	T
Polyphen		0.051	B
Vest4		0.29
MutPred		0.55		Gain of disorder (P = 0.1249)
MVP		0.95
MPC		0.074
ClinPred		0.26	T
GERP RS		3.4
Varity_R		0.13
gMVP		0.28
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: rs751310423; hg19: chr7-142639553; COSMIC: COSV100786861; COSMIC: COSV100786861;