12-52171420-T-C

Position:

chr12-52171420-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_182507.3(KRT80):c.1337A>G(p.Gln446Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,605,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

KRT80
NM_182507.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.31

Variant links:

Genes affected

KRT80 (HGNC:27056): (keratin 80) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This gene's expression profile shows that it encodes a type II epithelial keratin, although structurally the encoded protein is more like a type II hair keratin. This protein is involved in cell differentiation, localizing near desmosomal plaques in earlier stages of differentiation but then dispersing throughout the cytoplasm in terminally differentiating cells. The type II keratins are clustered in a region of chromosome 12q13. Two transcript variants encoding two different fully functional isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

KRT80 links:

KRT80 (HGNC:):

KRT80 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39521173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT80	NM_182507.3 linkuse as main transcript	c.1337A>G	p.Gln446Arg	missense_variant	9/9	ENST00000394815.3	NP_872313.2	Q6KB66-1
KRT80	XM_005268676.4 linkuse as main transcript	c.1442A>G	p.Gln481Arg	missense_variant	7/7		XP_005268733.1
KRT80	NM_001081492.2 linkuse as main transcript	c.*103A>G		3_prime_UTR_variant	9/9		NP_001074961.1	Q6KB66-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRT80	ENST00000394815.3 linkuse as main transcript	c.1337A>G	p.Gln446Arg	missense_variant	9/9	1	NM_182507.3	ENSP00000378292.2	Q6KB66-1
KRT80	ENST00000313234.9 linkuse as main transcript	c.*103A>G		3_prime_UTR_variant	9/9	1		ENSP00000369361.2	Q6KB66-2
KRT80	ENST00000466011.1 linkuse as main transcript	n.1493A>G		non_coding_transcript_exon_variant	7/7	2
LINC00592	ENST00000640420.1 linkuse as main transcript	n.413+6469T>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243250

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131328

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453364

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000456

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.1337A>G (p.Q446R) alteration is located in exon 9 (coding exon 9) of the KRT80 gene. This alteration results from a A to G substitution at nucleotide position 1337, causing the glutamine (Q) at amino acid position 446 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0015

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.49

M_CAP

Benign

0.071

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.59

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

0.98

Vest4

0.48

MutPred

0.19

Gain of MoRF binding (P = 0.0599);

MVP

0.70

MPC

0.13

ClinPred

0.54

GERP RS

4.5

Varity_R

0.18

gMVP

0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over