rs56997521

Variant names:

• chr12-52898743-C-T
• rs56997521
• NM_002273.4:c.1138G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002273.4(KRT8):​c.1138G>A​(p.Val380Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000751 in 1,614,206 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (9 hom.)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 4.06
• Publications: 7 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]

MIR9898 (HGNC:53990): (microRNA 9898) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01279372).
• BP6: Variant 12-52898743-C-T is Benign according to our data. Variant chr12-52898743-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 66524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002273.4. 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
	KRT8	NM_002273.4	MANE Select	c.1138G>A	p.Val380Ile	missense	Exon 6 of 8	NP_002264.1	P05787-1
	KRT8	NM_001256282.2		c.1222G>A	p.Val408Ile	missense	Exon 7 of 9	NP_001243211.1	P05787-2
	KRT8	NM_001256293.2		c.1138G>A	p.Val380Ile	missense	Exon 7 of 9	NP_001243222.1	P05787-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT8	ENST00000692008.1	MANE Select	c.1138G>A	p.Val380Ile	missense	Exon 6 of 8	ENSP00000509398.1	P05787-1
	KRT8	ENST00000552150.5	TSL:1	c.1222G>A	p.Val408Ile	missense	Exon 7 of 9	ENSP00000449404.1	P05787-2
	KRT8	ENST00000871797.1		c.1138G>A	p.Val380Ile	missense	Exon 6 of 8	ENSP00000541856.1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00153 AC: 384 AN: 251464 AF XY: 0.00200

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000780 AC: 1140 AN: 1461876 Hom.: 9 Cov.: 33 AF XY: 0.00102 AC XY: 741 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00344 AC: 90 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00738 AC: 637 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5762

European-Non Finnish (NFE) AF: 0.000246 AC: 273 AN: 1112010

Other (OTH) AF: 0.00128 AC: 77 AN: 60392

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74482

African (AFR) AF: 0.0000722 AC: 3 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.00161 AC: 196

EpiCase AF: 0.000654

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Benign	0.21	T
Polyphen		0.033	B
Vest4		0.22
MVP		0.90
MPC		0.42
ClinPred		0.024	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.12
gMVP		0.82
Mutation Taster		=97/3	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: rs56997521; hg19: chr12-53292527;