17-40930073-T-C

Position:

• chr17-40930073-T-C

Variant summary

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

The NM_015515.5(KRT23):​c.503A>G​(p.Lys168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000014 (0 hom.)
• Consequence: KRT23 NM_015515.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

Genes affected

KRT23 (HGNC:6438): (keratin 23) The protein encoded by this gene is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. The type I cytokeratin genes are clustered in a region of chromosome 17q12-q21. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ENSG00000234477 (HGNC:):

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=0.08551848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT23	NM_015515.5	c.503A>G	p.Lys168Arg	missense_variant	4/9	ENST00000209718.8	NP_056330.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT23	ENST00000209718.8	c.503A>G	p.Lys168Arg	missense_variant	4/9	1	NM_015515.5	ENSP00000209718.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

GnomAD4 genome Cov.: 32

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

Oct 24, 2024

The c.503A>G (p.K168R) alteration is located in exon 4 (coding exon 3) of the KRT23 gene. This alteration results from a A to G substitution at nucleotide position 503, causing the lysine (K) at amino acid position 168 to be replaced by an arginine (R). 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	0.074
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.57	N;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.9	N;N;.
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.12	B;.;.
Vest4		0.083
MutPred		0.54		Loss of ubiquitination at K168 (P = 0.0183);.;.;
MVP		0.23
MPC		0.44
ClinPred		0.68	D
GERP RS		3.4
Varity_R		0.038
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1909544465; hg19: chr17-39086325;