17-40818899-T-C

Variant names:

• chr17-40818899-T-C
• rs1217847176
• NM_000421.5:c.1636A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000421.5(KRT10):​c.1636A>G​(p.Ser546Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,180,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S546R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00047 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT10 NM_000421.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.619
• Publications: 8 publications found

Genes affected

KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin 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. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]

KRT10-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028027594).
• BP6: Variant 17-40818899-T-C is Benign according to our data. Variant chr17-40818899-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1223538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000421.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	NM_000421.5	MANE Select	c.1636A>G	p.Ser546Gly	missense	Exon 7 of 8	NP_000412.4
	KRT10	NM_001379366.1		c.1636A>G	p.Ser546Gly	missense	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3
	KRT10-AS1	NR_160887.1		n.-246T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1636A>G	p.Ser546Gly	missense	Exon 7 of 8	ENSP00000269576.5	P13645
	KRT10	ENST00000635956.2	TSL:2	c.1636A>G	p.Ser546Gly	missense	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
	KRT10-AS1	ENST00000301665.10	TSL:2	n.-199T>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000293 AC: 25 AN: 85374 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000848

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000887

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00712 AC: 763 AN: 107222 AF XY: 0.00737

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00459

Gnomad EAS exome AF: 0.0197

Gnomad FIN exome AF: 0.00868

Gnomad NFE exome AF: 0.00666

Gnomad OTH exome AF: 0.00576

GnomAD4 exome AF: 0.000470 AC: 555 AN: 1180316 Hom.: 1 Cov.: 30 AF XY: 0.000583 AC XY: 338 AN XY: 579926

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00169 AC: 36 AN: 21308

American (AMR) AF: 0.00145 AC: 42 AN: 28876

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 22 AN: 19672

East Asian (EAS) AF: 0.00176 AC: 44 AN: 24996

South Asian (SAS) AF: 0.00254 AC: 135 AN: 53216

European-Finnish (FIN) AF: 0.000943 AC: 27 AN: 28618

Middle Eastern (MID) AF: 0.000714 AC: 3 AN: 4202

European-Non Finnish (NFE) AF: 0.000232 AC: 221 AN: 951810

Other (OTH) AF: 0.000525 AC: 25 AN: 47618

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000293 AC: 25 AN: 85466 Hom.: 0 Cov.: 23 AF XY: 0.000168 AC XY: 7 AN XY: 41602

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000844 AC: 13 AN: 15394

American (AMR) AF: 0.000101 AC: 1 AN: 9950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2276

East Asian (EAS) AF: 0.000888 AC: 2 AN: 2252

South Asian (SAS) AF: 0.000835 AC: 2 AN: 2396

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 124

European-Non Finnish (NFE) AF: 0.000133 AC: 6 AN: 45130

Other (OTH) AF: 0.00 AC: 0 AN: 1168

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00422 Hom.: 0

ExAC AF: 0.0112 AC: 1117

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.4
DANN	Benign	0.48
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.62
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.30		Loss of phosphorylation at S546 (P = 4e-04)
MPC		0.38
ClinPred		0.018	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.080
gMVP		0.25
Mutation Taster		=99/1	polymorphism

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: rs1217847176; hg19: chr17-38975151; COSMIC: COSV54088333; COSMIC: COSV54088333;