17-41047073-G-C

Position:

• chr17-41047073-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.195C>G​(p.Asp65Glu) 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: not found (cov: 31)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP2-1 NM_001123387.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

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=0.11641082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP2-1	NM_001123387.1	c.195C>G	p.Asp65Glu	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.195C>G	p.Asp65Glu	missense_variant	1/1	6	NM_001123387.1	ENSP00000375238.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.17e-7 AC: 1 AN: 1223944 Hom.: 0 Cov.: 23 AF XY: 0.00000166 AC XY: 1 AN XY: 600866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000193

GnomAD4 genome Cov.: 31

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

Sep 20, 2024

The c.195C>G (p.D65E) 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 195, causing the aspartic acid (D) at amino acid position 65 to be replaced by a glutamic acid (E). 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	0.27
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.47	N;N
REVEL	Benign	0.015
Sift	Benign	0.51	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0050	B;.
Vest4		0.19
MutPred		0.42		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.048
ClinPred		0.64	D
GERP RS		3.6
Varity_R		0.045
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

LitVar

Other links and lift over

dbSNP: rs1047286670; hg19: chr17-39203325;