rs2035875

Variant names:

• chr12-52902133-A-G
• rs2035875
• NM_002273.4:c.325-61T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-52902133-A-G
• chr12-52902133-A-T

Variant summary

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

The NM_002273.4(KRT8):​c.325-61T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,036,336 control chromosomes in the GnomAD database, including 148,037 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 0.50 (19383 hom., cov: 30)
  • Exomes 𝑓: 0.53 (128654 hom.)
• Consequence: KRT8 NM_002273.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.625
• Publications: 15 publications found

Genes affected

KRT8 (HGNC:6446): (keratin 8) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

KRT8 Gene-Disease associations (from GenCC):

• cirrhosis, familial

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT8	NM_002273.4	c.325-61T>C		intron_variant	Intron 1 of 7	ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2	c.409-61T>C		intron_variant	Intron 2 of 8		NP_001243211.1
KRT8	NM_001256293.2	c.325-61T>C		intron_variant	Intron 2 of 8		NP_001243222.1
KRT8	NR_045962.2	n.776-61T>C		intron_variant	Intron 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1	c.325-61T>C		intron_variant	Intron 1 of 7		NM_002273.4	ENSP00000509398.1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76047 AN: 151756 Hom.: 19345 Cov.: 30

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.505

GnomAD4 exome AF: 0.532 AC: 470898 AN: 884462 Hom.: 128654 Cov.: 12 AF XY: 0.538 AC XY: 249361 AN XY: 463164

African (AFR) AF: 0.441 AC: 9939 AN: 22532

American (AMR) AF: 0.679 AC: 28444 AN: 41918

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 11080 AN: 22488

East Asian (EAS) AF: 0.637 AC: 23366 AN: 36706

South Asian (SAS) AF: 0.697 AC: 51600 AN: 74052

European-Finnish (FIN) AF: 0.430 AC: 15988 AN: 37188

Middle Eastern (MID) AF: 0.552 AC: 2160 AN: 3914

European-Non Finnish (NFE) AF: 0.508 AC: 306590 AN: 603982

Other (OTH) AF: 0.521 AC: 21731 AN: 41682

GnomAD4 genome AF: 0.501 AC: 76133 AN: 151874 Hom.: 19383 Cov.: 30 AF XY: 0.504 AC XY: 37399 AN XY: 74192

African (AFR) AF: 0.442 AC: 18328 AN: 41422

American (AMR) AF: 0.570 AC: 8701 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1752 AN: 3472

East Asian (EAS) AF: 0.623 AC: 3203 AN: 5138

South Asian (SAS) AF: 0.729 AC: 3500 AN: 4804

European-Finnish (FIN) AF: 0.412 AC: 4337 AN: 10516

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.508 AC: 34509 AN: 67952

Other (OTH) AF: 0.509 AC: 1073 AN: 2110

Alfa AF: 0.516 Hom.: 10450

Bravo AF: 0.512

Asia WGS AF: 0.613 AC: 2130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.70
PhyloP100		-0.63
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: rs2035875; hg19: chr12-53295917; COSMIC: COSV53178462; COSMIC: COSV53178462;