17-40928252-T-C

Variant names:

• chr17-40928252-T-C
• rs9257
• NM_015515.5:c.907A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015515.5(KRT23):​c.907A>G​(p.Thr303Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,613,648 control chromosomes in the GnomAD database, including 156,198 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.47 (17682 hom., cov: 31)
  • Exomes 𝑓: 0.43 (138516 hom.)
• Consequence: KRT23 NM_015515.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.353
• Publications: 39 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0328584E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015515.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT23	NM_015515.5	MANE Select	c.907A>G	p.Thr303Ala	missense	Exon 6 of 9	NP_056330.3
	KRT23	NM_001282433.2		c.496A>G	p.Thr166Ala	missense	Exon 5 of 8	NP_001269362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT23	ENST00000209718.8	TSL:1 MANE Select	c.907A>G	p.Thr303Ala	missense	Exon 6 of 9	ENSP00000209718.3
	KRT23	ENST00000462312.5	TSL:1	n.*225A>G		non_coding_transcript_exon	Exon 4 of 7	ENSP00000462335.1
	KRT23	ENST00000582754.5	TSL:1	n.1139A>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71772 AN: 151778 Hom.: 17662 Cov.: 31

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.489 AC: 122785 AN: 251344 AF XY: 0.484

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.653

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.426 AC: 622154 AN: 1461752 Hom.: 138516 Cov.: 54 AF XY: 0.430 AC XY: 312640 AN XY: 727186

African (AFR) AF: 0.566 AC: 18963 AN: 33476

American (AMR) AF: 0.638 AC: 28552 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12054 AN: 26136

East Asian (EAS) AF: 0.729 AC: 28929 AN: 39700

South Asian (SAS) AF: 0.579 AC: 49943 AN: 86254

European-Finnish (FIN) AF: 0.339 AC: 18099 AN: 53410

Middle Eastern (MID) AF: 0.577 AC: 3323 AN: 5762

European-Non Finnish (NFE) AF: 0.392 AC: 435617 AN: 1111900

Other (OTH) AF: 0.442 AC: 26674 AN: 60390

GnomAD4 genome AF: 0.473 AC: 71837 AN: 151896 Hom.: 17682 Cov.: 31 AF XY: 0.477 AC XY: 35412 AN XY: 74232

African (AFR) AF: 0.562 AC: 23291 AN: 41420

American (AMR) AF: 0.569 AC: 8684 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1617 AN: 3468

East Asian (EAS) AF: 0.712 AC: 3680 AN: 5170

South Asian (SAS) AF: 0.591 AC: 2843 AN: 4812

European-Finnish (FIN) AF: 0.341 AC: 3600 AN: 10548

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26654 AN: 67914

Other (OTH) AF: 0.469 AC: 987 AN: 2104

Alfa AF: 0.431 Hom.: 68479

Bravo AF: 0.496

TwinsUK AF: 0.383 AC: 1422

ALSPAC AF: 0.387 AC: 1492

ESP6500AA AF: 0.560 AC: 2468

ESP6500EA AF: 0.394 AC: 3385

ExAC AF: 0.485 AC: 58869

Asia WGS AF: 0.617 AC: 2146 AN: 3478

EpiCase AF: 0.412

EpiControl AF: 0.412

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.3
DANN	Benign	0.69
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.35
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.21
Sift	Benign	0.72	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.12
ClinPred		0.0025	T
GERP RS		-1.5
Varity_R		0.048
gMVP		0.22
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9257; hg19: chr17-39084504; COSMIC: COSV52927747; COSMIC: COSV52927747;