17-41567345-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000226.4(KRT9):c.1800C>T(p.Tyr600=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000895 in 1,613,626 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00092 (12 hom.)
• Consequence: KRT9 NM_000226.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.173

Genes affected

KRT9 (HGNC:6447): (keratin 9) This gene encodes the type I keratin 9, an intermediate filament chain expressed only in the terminally differentiated epidermis of palms and soles. Mutations in this gene cause epidermolytic palmoplantar keratoderma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-41567345-G-A is Benign according to our data. Variant chr17-41567345-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 323114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.173 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000657 (100/152100) while in subpopulation SAS AF= 0.0027 (13/4812). AF 95% confidence interval is 0.0016. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT9	NM_000226.4	c.1800C>T	p.Tyr600=	synonymous_variant	7/8	ENST00000246662.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT9	ENST00000246662.9	c.1800C>T	p.Tyr600=	synonymous_variant	7/8	1	NM_000226.4	P1
KRT9	ENST00000588431.1	c.1101C>T	p.Tyr367=	synonymous_variant	8/9	1

Frequencies

GnomAD3 genomes AF: 0.000658 AC: 100 AN: 151982 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00104 AC: 256 AN: 247298 Hom.: 3 AF XY: 0.00128 AC XY: 171 AN XY: 133962

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00377

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.000920 AC: 1345 AN: 1461526 Hom.: 12 Cov.: 146 AF XY: 0.000990 AC XY: 720 AN XY: 727050

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00360

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000830

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152100 Hom.: 0 Cov.: 31 AF XY: 0.000646 AC XY: 48 AN XY: 74340

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.000593

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 29, 2022

- -

Palmoplantar keratoderma, epidermolytic Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	2.4
Dann	Benign	0.87

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: rs148193621; hg19: chr17-39723597; COSMIC: COSV99879338;