21-30613856-A-G

Position:

• chr21-30613856-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181602.2(KRTAP6-1):​c.49T>C​(p.Phe17Leu) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRTAP6-1 NM_181602.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.214

Genes affected

KRTAP6-1 (HGNC:18931): (keratin associated protein 6-1) Predicted to be involved in keratinization. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06536052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP6-1	NM_181602.2	c.49T>C	p.Phe17Leu	missense_variant	1/1	ENST00000329122.2	NP_853633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP6-1	ENST00000329122.2	c.49T>C	p.Phe17Leu	missense_variant	1/1		NM_181602.2	ENSP00000332690	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.49T>C (p.F17L) alteration is located in exon 1 (coding exon 1) of the KRTAP6-1 gene. This alteration results from a T to C substitution at nucleotide position 49, causing the phenylalanine (F) at amino acid position 17 to be replaced by a leucine (L). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.039
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.26		Gain of disorder (P = 0.0742);
MVP		0.11
MPC		0.16
ClinPred		0.11	T
GERP RS		-4.3
Varity_R		0.30
gMVP		0.023

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: chr21-31986175;