rs77688767

chr17-41568340-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000226.4(KRT9):c.1216T>C(p.Cys406Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,614,182 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (5 hom.)
• Consequence: KRT9 NM_000226.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2 O:1
• Conservation: PhyloP100: -0.118

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012534499).
• BP6: Variant 17-41568340-A-G is Benign according to our data. Variant chr17-41568340-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66145.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1, not_provided=1}. Variant chr17-41568340-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000584 (89/152290) while in subpopulation EAS AF= 0.016 (83/5188). AF 95% confidence interval is 0.0132. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT9	NM_000226.4	c.1216T>C	p.Cys406Arg	missense_variant	6/8	ENST00000246662.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT9	ENST00000246662.9	c.1216T>C	p.Cys406Arg	missense_variant	6/8	1	NM_000226.4	P1
KRT9	ENST00000588431.1	c.517T>C	p.Cys173Arg	missense_variant	7/9	1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152172 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00123 AC: 309 AN: 251492 Hom.: 3 AF XY: 0.00117 AC XY: 159 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000510 AC: 746 AN: 1461892 Hom.: 5 Cov.: 33 AF XY: 0.000539 AC XY: 392 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152290 Hom.: 0 Cov.: 31 AF XY: 0.000618 AC XY: 46 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000881 Hom.: 1

Bravo AF: 0.000941

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Palmoplantar keratoderma, epidermolytic Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 29, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D
Eigen	Benign	0.0094
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.0049	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0060	D;.
Sift4G	Benign	0.53	T;T
Polyphen		0.97	D;.
Vest4		0.32
MVP		0.93
MPC		0.53
ClinPred		0.15	T
GERP RS		2.7
Varity_R		0.75
gMVP		0.36

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: rs77688767; hg19: chr17-39724592; COSMIC: COSV55855276;