17-40699553-A-G

Position:

• chr17-40699553-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019016.3(KRT24):​c.1252T>C​(p.Trp418Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,613,934 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0082 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: KRT24 NM_019016.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.696

Genes affected

KRT24 (HGNC:18527): (keratin 24) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017380416).
• BP6: Variant 17-40699553-A-G is Benign according to our data. Variant chr17-40699553-A-G is described in ClinVar as [Benign]. Clinvar id is 710112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00821 (1250/152284) while in subpopulation AFR AF= 0.0272 (1130/41528). AF 95% confidence interval is 0.0259. There are 15 homozygotes in gnomad4. There are 558 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT24	NM_019016.3	c.1252T>C	p.Trp418Arg	missense_variant	6/8	ENST00000264651.3	NP_061889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT24	ENST00000264651.3	c.1252T>C	p.Trp418Arg	missense_variant	6/8	1	NM_019016.3	ENSP00000264651	P1

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152166 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00242 AC: 609 AN: 251452 Hom.: 3 AF XY: 0.00160 AC XY: 217 AN XY: 135902

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00121 AC: 1762 AN: 1461650 Hom.: 30 Cov.: 34 AF XY: 0.00113 AC XY: 824 AN XY: 727130

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00821 AC: 1250 AN: 152284 Hom.: 15 Cov.: 32 AF XY: 0.00749 AC XY: 558 AN XY: 74456

Gnomad4 AFR AF: 0.0272

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00220 Hom.: 7

Bravo AF: 0.00949

ESP6500AA AF: 0.0256 AC: 113

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.0
DANN	Benign	0.53
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-4.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	6.9	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.18		Gain of disorder (P = 0.0109);
MVP		0.13
MPC		0.11
ClinPred		0.0041	T
GERP RS		2.2
Varity_R		0.067
gMVP		0.48

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: rs12946793; hg19: chr17-38855805; COSMIC: COSV99079771;