11-1597797-A-C

Variant names:

• chr11-1597797-A-C
• rs779300507
• NM_001004325.2:c.454T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001004325.2(KRTAP5-2):​c.454T>G​(p.Cys152Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KRTAP5-2 NM_001004325.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

Genes affected

KRTAP5-2 (HGNC:23597): (keratin associated protein 5-2) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP5-AS1 (HGNC:27877): (KRTAP5-1/KRTAP5-2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35169834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP5-2	NM_001004325.2	c.454T>G	p.Cys152Gly	missense_variant	Exon 1 of 1	ENST00000412090.2	NP_001004325.1
KRTAP5-AS1	NR_021489.2	n.878A>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP5-2	ENST00000412090.2	c.454T>G	p.Cys152Gly	missense_variant	Exon 1 of 1	6	NM_001004325.2	ENSP00000400041.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251490 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461756 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

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: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.454T>G (p.C152G) alteration is located in exon 1 (coding exon 1) of the KRTAP5-2 gene. This alteration results from a T to G substitution at nucleotide position 454, causing the cysteine (C) at amino acid position 152 to be replaced by a glycine (G). 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	0.32
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.73
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.51	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	M
PROVEAN	Pathogenic	-9.5	D
REVEL	Benign	0.10
Sift4G	Uncertain	0.020	D
Polyphen		0.21	B
Vest4		0.58
MutPred		0.40		Loss of stability (P = 0.0467);
MVP		0.33
MPC		0.11
ClinPred		0.44	T
GERP RS		3.3
Varity_R		0.73
gMVP		0.090

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: rs779300507; hg19: chr11-1619027;