7-128877063-C-T

Variant names:

• chr7-128877063-C-T
• NM_001366122.1:c.4867G>A

Variant summary

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

The NM_001366122.1(KCP):​c.4867G>A​(p.Glu1623Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,376,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: KCP NM_001366122.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691
• Publications: 0 publications found

Genes affected

KCP (HGNC:17585): (kielin cysteine rich BMP regulator) Predicted to act upstream of or within hematopoietic progenitor cell differentiation and positive regulation of BMP signaling pathway. Predicted to be located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

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=0.10611421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCP	NM_001366122.1	c.4867G>A	p.Glu1623Lys	missense_variant	Exon 40 of 40	ENST00000610776.5	NP_001353051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCP	ENST00000610776.5	c.4867G>A	p.Glu1623Lys	missense_variant	Exon 40 of 40	5	NM_001366122.1	ENSP00000479679.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1376380 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 678760

African (AFR) AF: 0.00 AC: 0 AN: 30036

American (AMR) AF: 0.00 AC: 0 AN: 27558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23942

East Asian (EAS) AF: 0.00 AC: 0 AN: 35458

South Asian (SAS) AF: 0.00 AC: 0 AN: 75574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073124

Other (OTH) AF: 0.0000175 AC: 1 AN: 56990

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4492G>A (p.E1498K) alteration is located in exon 36 (coding exon 36) of the KCP gene. This alteration results from a G to A substitution at nucleotide position 4492, causing the glutamic acid (E) at amino acid position 1498 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.011	T;.;T
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.11	T;T;T
PhyloP100		0.69
PrimateAI	Benign	0.38	T
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.15
MVP		0.22
GERP RS		2.1
Varity_R		0.027
gMVP		0.62
Mutation Taster		=100/0	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

hg19: chr7-128517117;