17-41586829-G-T

Variant names:

• chr17-41586829-G-T
• NM_000526.5:c.6C>A
• KRT14 p.Thr2Thr

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000526.5(KRT14):​c.6C>A​(p.Thr2Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T2T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT14 NM_000526.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• Publications: 0 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: Genomics England PanelApp, Orphanet, Ambry Genetics
• Naegeli-Franceschetti-Jadassohn syndrome

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=2.59 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT14	NM_000526.5	MANE Select	c.6C>A	p.Thr2Thr	synonymous	Exon 1 of 8	NP_000517.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT14	ENST00000167586.7	TSL:1 MANE Select	c.6C>A	p.Thr2Thr	synonymous	Exon 1 of 8	ENSP00000167586.6	P02533

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1432398 Hom.: 0 Cov.: 73 AF XY: 0.00 AC XY: 0 AN XY: 710580

African (AFR) AF: 0.00 AC: 0 AN: 32880

American (AMR) AF: 0.00 AC: 0 AN: 41004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 38192

South Asian (SAS) AF: 0.00 AC: 0 AN: 83168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099790

Other (OTH) AF: 0.00 AC: 0 AN: 59186

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		2.6
PromoterAI		0.076	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-39743081;