chr12-52171426-A-C

Variant names:

• chr12-52171426-A-C
• rs765254834
• NM_182507.3:c.1331T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_182507.3(KRT80):​c.1331T>G​(p.Phe444Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000715 in 1,608,194 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F444V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (1 hom.)
• Consequence: KRT80 NM_182507.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87
• Publications: 0 publications found

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]

LINC00592 (HGNC:27474): (long intergenic non-protein coding RNA 592)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011362284).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182507.3. 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
	KRT80	NM_182507.3	MANE Select	c.1331T>G	p.Phe444Cys	missense	Exon 9 of 9	NP_872313.2	Q6KB66-1
	KRT80	NM_001081492.2		c.*97T>G		3_prime_UTR	Exon 9 of 9	NP_001074961.1	Q6KB66-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT80	ENST00000394815.3	TSL:1 MANE Select	c.1331T>G	p.Phe444Cys	missense	Exon 9 of 9	ENSP00000378292.2	Q6KB66-1
	KRT80	ENST00000313234.9	TSL:1	c.*97T>G		3_prime_UTR	Exon 9 of 9	ENSP00000369361.2	Q6KB66-2
	KRT80	ENST00000466011.1	TSL:2	n.1487T>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151660 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.000381 AC: 94 AN: 246778 AF XY: 0.000262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.0000762 AC: 111 AN: 1456534 Hom.: 1 Cov.: 30 AF XY: 0.0000594 AC XY: 43 AN XY: 724166

African (AFR) AF: 0.0000300 AC: 1 AN: 33292

American (AMR) AF: 0.00236 AC: 104 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109242

Other (OTH) AF: 0.0000665 AC: 4 AN: 60136

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151660 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74042

African (AFR) AF: 0.00 AC: 0 AN: 41278

American (AMR) AF: 0.000263 AC: 4 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000206 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0048	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.063	T
Polyphen		0.45	P
Vest4		0.25
MutPred		0.18		Gain of ubiquitination at K442 (P = 0.14)
MVP		0.64
MPC		0.22
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.32
Mutation Taster		=97/3	polymorphism

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: rs765254834; hg19: chr12-52565210;