12-52646627-T-G

Variant names:

• chr12-52646627-T-G
• rs2232559
• NM_000423.3:c.1469+113A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000423.3(KRT2):​c.1469+113A>C variant causes a intron 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT2 NM_000423.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 9 publications found

Genes affected

KRT2 (HGNC:6439): (keratin 2) 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 expressed largely in the upper spinous layer of epidermal keratinocytes and mutations in this gene 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]

KRT2 Gene-Disease associations (from GenCC):

• superficial epidermolytic ichthyosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT2	NM_000423.3	c.1469+113A>C		intron_variant	Intron 7 of 8	ENST00000309680.4	NP_000414.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT2	ENST00000309680.4	c.1469+113A>C		intron_variant	Intron 7 of 8	1	NM_000423.3	ENSP00000310861.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 987532 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 508156

African (AFR) AF: 0.00 AC: 0 AN: 24272

American (AMR) AF: 0.00 AC: 0 AN: 40994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22770

East Asian (EAS) AF: 0.00 AC: 0 AN: 36750

South Asian (SAS) AF: 0.00 AC: 0 AN: 75482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3372

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 696474

Other (OTH) AF: 0.00 AC: 0 AN: 44884

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.011
DANN	Benign	0.54
PhyloP100		-2.0

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: rs2232559; hg19: chr12-53040411;