rs11551758

Variant names:

• chr17-41586646-G-A
• rs11551758
• NM_000526.5:c.189C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-41586646-G-A
• chr17-41586646-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000526.5(KRT14):​c.189C>T​(p.Cys63Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 151,994 control chromosomes in the GnomAD database, including 26,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26008 hom., cov: 32)
  • Exomes 𝑓: 0.59 (255401 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT14 NM_000526.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -2.51
• Publications: 7 publications found

Genes affected

KRT14 (HGNC:6416): (keratin 14) This gene encodes a member of the keratin family, the most diverse group of intermediate filaments. This gene product, a type I keratin, is usually found as a heterotetramer with two keratin 5 molecules, a type II keratin. Together they form the cytoskeleton of epithelial cells. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. At least one pseudogene has been identified at 17p12-p11. [provided by RefSeq, Jul 2008]

KRT14 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex 1A, generalized severe

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp
• Naegeli-Franceschetti-Jadassohn syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
• dermatopathia pigmentosa reticularis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 1B, generalized intermediate

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 1C, localized

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 2F, with mottled pigmentation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-41586646-G-A is Benign according to our data. Variant chr17-41586646-G-A is described in ClinVar as Benign. ClinVar VariationId is 66331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000526.5. 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
	KRT14	NM_000526.5	MANE Select	c.189C>T	p.Cys63Cys	synonymous	Exon 1 of 8	NP_000517.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT14	ENST00000167586.7	TSL:1 MANE Select	c.189C>T	p.Cys63Cys	synonymous	Exon 1 of 8	ENSP00000167586.6

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87366 AN: 151876 Hom.: 25992 Cov.: 32

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.561

GnomAD2 exomes AF: 0.631 AC: 135116 AN: 214136 AF XY: 0.629

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.763

Gnomad ASJ exome AF: 0.555

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.587

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.586 AC: 851893 AN: 1453780 Hom.: 255401 Cov.: 91 AF XY: 0.589 AC XY: 425807 AN XY: 722740

African (AFR) AF: 0.472 AC: 15699 AN: 33250

American (AMR) AF: 0.762 AC: 32821 AN: 43068

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14624 AN: 25992

East Asian (EAS) AF: 0.959 AC: 37780 AN: 39376

South Asian (SAS) AF: 0.715 AC: 61402 AN: 85826

European-Finnish (FIN) AF: 0.664 AC: 34976 AN: 52660

Middle Eastern (MID) AF: 0.503 AC: 2805 AN: 5576

European-Non Finnish (NFE) AF: 0.557 AC: 616704 AN: 1108028

Other (OTH) AF: 0.585 AC: 35082 AN: 60004

GnomAD4 genome AF: 0.575 AC: 87426 AN: 151994 Hom.: 26008 Cov.: 32 AF XY: 0.584 AC XY: 43401 AN XY: 74288

African (AFR) AF: 0.473 AC: 19602 AN: 41462

American (AMR) AF: 0.679 AC: 10366 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1948 AN: 3472

East Asian (EAS) AF: 0.949 AC: 4898 AN: 5162

South Asian (SAS) AF: 0.736 AC: 3547 AN: 4822

European-Finnish (FIN) AF: 0.659 AC: 6962 AN: 10560

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38066 AN: 67918

Other (OTH) AF: 0.565 AC: 1195 AN: 2116

Alfa AF: 0.562 Hom.: 7681

Bravo AF: 0.574

Asia WGS AF: 0.823 AC: 2857 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Epidermolysis bullosa simplex 1A, generalized severe;C0080333:Epidermolysis bullosa simplex 1C, localized;C0343111:Naegeli-Franceschetti-Jadassohn syndrome;C0406778:Dermatopathia pigmentosa reticularis;C3715082:Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive;C5561924:Epidermolysis bullosa simplex, Koebner type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.95
DANN	Benign	0.56
PhyloP100		-2.5
PromoterAI		0.0050	Neutral
Mutation Taster		=95/5	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: rs11551758; hg19: chr17-39742898; COSMIC: COSV51421109; COSMIC: COSV51421109;