17-41047063-G-C

Position:

• chr17-41047063-G-C

Variant summary

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

The NM_001123387.1(KRTAP2-1):​c.205C>G​(p.Leu69Val) 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: KRTAP2-1 NM_001123387.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

Genes affected

KRTAP2-1 (HGNC:16775): (keratin associated protein 2-1) 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=0.18391475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP2-1	NM_001123387.1	c.205C>G	p.Leu69Val	missense_variant	1/1	ENST00000391419.3	NP_001116859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP2-1	ENST00000391419.3	c.205C>G	p.Leu69Val	missense_variant	1/1	6	NM_001123387.1	ENSP00000375238.3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151780 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 23

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000659 AC: 1 AN: 151780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74096

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Nov 09, 2024

The c.205C>G (p.L69V) alteration is located in exon 1 (coding exon 1) of the KRTAP2-1 gene. This alteration results from a C to G substitution at nucleotide position 205, causing the leucine (L) at amino acid position 69 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	0.093
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0018	T;.
Eigen	Benign	-0.015
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.069
Sift	Benign	0.13	T;D
Sift4G	Benign	0.17	T;T
Polyphen		0.0030	B;.
Vest4		0.26
MutPred		0.56		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.13
ClinPred		0.60	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.032

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

LitVar

Other links and lift over

dbSNP: rs2012857663; hg19: chr17-39203315;