21-30598840-T-A

Variant names:

• chr21-30598840-T-A
• NM_181604.2:c.35A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181604.2(KRTAP6-2):​c.35A>T​(p.Asp12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D12G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRTAP6-2 NM_181604.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

Genes affected

KRTAP6-2 (HGNC:18932): (keratin associated protein 6-2) Enables identical protein binding activity. Predicted to be involved in keratinization. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14864314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP6-2	NM_181604.2	c.35A>T	p.Asp12Val	missense_variant	Exon 1 of 1	ENST00000334897.4	NP_853635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP6-2	ENST00000334897.4	c.35A>T	p.Asp12Val	missense_variant	Exon 1 of 1	6	NM_181604.2	ENSP00000334560.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35A>T (p.D12V) alteration is located in exon 1 (coding exon 1) of the KRTAP6-2 gene. This alteration results from a A to T substitution at nucleotide position 35, causing the aspartic acid (D) at amino acid position 12 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.68
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.065	N
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Benign	0.093
Sift4G	Uncertain	0.045	D
Polyphen		0.083	B
Vest4		0.29
MutPred		0.39		Gain of sheet (P = 0.0125);
MVP		0.11
MPC		0.088
ClinPred		0.41	T
GERP RS		3.5
Varity_R		0.41
gMVP		0.098

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-31971159;