12-52676904-G-A

Variant names:

• chr12-52676904-G-A
• rs597685
• NM_006121.4:c.1254+155C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006121.4(KRT1):​c.1254+155C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 152,050 control chromosomes in the GnomAD database, including 9,072 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9072 hom., cov: 33)
• Consequence: KRT1 NM_006121.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.61
• Publications: 12 publications found

Genes affected

KRT1 (HGNC:6412): (keratin 1) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the spinous and granular layers of the epidermis with family member KRT10 and mutations in these genes have been associated with bullous congenital ichthyosiform erythroderma. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT1 Gene-Disease associations (from GenCC):

• annular epidermolytic ichthyosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, PanelApp Australia
• ichthyosis hystrix of Curth-Macklin

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, PanelApp Australia
• diffuse nonepidermolytic palmoplantar keratoderma

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• epidermolytic ichthyosis

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, Genomics England PanelApp, PanelApp Australia
• ichthyosis, annular epidermolytic 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ichthyosis, annular epidermolytic, 2

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• congenital reticular ichthyosiform erythroderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive congenital ichthyosis 11

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006121.4. 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
	KRT1	NM_006121.4	MANE Select	c.1254+155C>T		intron	N/A	NP_006112.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT1	ENST00000252244.3	TSL:1 MANE Select	c.1254+155C>T		intron	N/A	ENSP00000252244.3
	KRT1	ENST00000548765.1	TSL:2	n.328+155C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.342 AC: 52014 AN: 151932 Hom.: 9072 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.349

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.342 AC: 52018 AN: 152050 Hom.: 9072 Cov.: 33 AF XY: 0.344 AC XY: 25590 AN XY: 74322

African (AFR) AF: 0.310 AC: 12855 AN: 41484

American (AMR) AF: 0.294 AC: 4494 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1175 AN: 3468

East Asian (EAS) AF: 0.587 AC: 3034 AN: 5168

South Asian (SAS) AF: 0.348 AC: 1678 AN: 4824

European-Finnish (FIN) AF: 0.389 AC: 4109 AN: 10556

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23740 AN: 67976

Other (OTH) AF: 0.345 AC: 723 AN: 2098

Alfa AF: 0.343 Hom.: 29234

Bravo AF: 0.336

Asia WGS AF: 0.405 AC: 1411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.41
PhyloP100		-2.6
Mutation Taster		=100/0	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: rs597685; hg19: chr12-53070688;