rs1555171425

Variant names:

• chr12-52678604-A-T
• rs1555171425
• NM_006121.4:c.744T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006121.4(KRT1):​c.744T>A​(p.Asp248Glu) variant causes a missense 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT1 NM_006121.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.553
• Publications: 0 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: Orphanet, Genomics England PanelApp, G2P, PanelApp Australia
• ichthyosis hystrix of Curth-Macklin

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

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

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, PanelApp Australia, Orphanet, Genomics England PanelApp
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07284123).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT1	NM_006121.4	MANE Select	c.744T>A	p.Asp248Glu	missense	Exon 2 of 9	NP_006112.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT1	ENST00000252244.3	TSL:1 MANE Select	c.744T>A	p.Asp248Glu	missense	Exon 2 of 9	ENSP00000252244.3	P04264

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Abnormality of the skin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.061
DANN	Benign	0.22
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.74	N
PhyloP100		-0.55
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.078	B
Vest4		0.095
MutPred		0.51		Loss of MoRF binding (P = 0.1339)
MVP		0.80
MPC		0.46
ClinPred		0.13	T
GERP RS		0.80
Varity_R		0.12
gMVP		0.28
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555171425; hg19: chr12-53072388;