12-52677598-A-C

Variant names:

• chr12-52677598-A-C
• rs2741159
• NM_006121.4:c.963+52T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006121.4(KRT1):​c.963+52T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,603,488 control chromosomes in the GnomAD database, including 122,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11317 hom., cov: 32)
  • Exomes 𝑓: 0.38 (111501 hom.)
• Consequence: KRT1 NM_006121.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.67
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-52677598-A-C is Benign according to our data. Variant chr12-52677598-A-C is described in ClinVar as Benign. ClinVar VariationId is 66667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.406 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.963+52T>G		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.963+52T>G		intron	N/A	ENSP00000252244.3
	KRT1	ENST00000548765.1	TSL:2	n.-81T>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57099 AN: 151982 Hom.: 11297 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.384 AC: 557323 AN: 1451388 Hom.: 111501 Cov.: 31 AF XY: 0.380 AC XY: 274823 AN XY: 722718

African (AFR) AF: 0.366 AC: 12154 AN: 33248

American (AMR) AF: 0.347 AC: 15508 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 10034 AN: 26080

East Asian (EAS) AF: 0.0125 AC: 494 AN: 39656

South Asian (SAS) AF: 0.256 AC: 22006 AN: 86008

European-Finnish (FIN) AF: 0.412 AC: 22000 AN: 53412

Middle Eastern (MID) AF: 0.332 AC: 1912 AN: 5756

European-Non Finnish (NFE) AF: 0.409 AC: 451352 AN: 1102516

Other (OTH) AF: 0.364 AC: 21863 AN: 59998

GnomAD4 genome AF: 0.376 AC: 57151 AN: 152100 Hom.: 11317 Cov.: 32 AF XY: 0.369 AC XY: 27422 AN XY: 74352

African (AFR) AF: 0.365 AC: 15140 AN: 41478

American (AMR) AF: 0.373 AC: 5701 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1329 AN: 3470

East Asian (EAS) AF: 0.0202 AC: 105 AN: 5186

South Asian (SAS) AF: 0.259 AC: 1247 AN: 4816

European-Finnish (FIN) AF: 0.408 AC: 4308 AN: 10562

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.410 AC: 27855 AN: 67980

Other (OTH) AF: 0.370 AC: 782 AN: 2116

Alfa AF: 0.360 Hom.: 4692

Bravo AF: 0.374

Asia WGS AF: 0.233 AC: 809 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.19
DANN	Benign	0.60
PhyloP100		-1.7
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: rs2741159; hg19: chr12-53071382;