12-52171710-C-A

Variant names:

• chr12-52171710-C-A
• rs770804000
• NM_182507.3:c.1182G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182507.3(KRT80):​c.1182G>T​(p.Met394Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,167,186 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000076 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: KRT80 NM_182507.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1182G>T	p.Met394Ile	missense	Exon 8 of 9	NP_872313.2	Q6KB66-1
	KRT80	NM_001081492.2		c.1182G>T	p.Met394Ile	missense	Exon 8 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.1182G>T	p.Met394Ile	missense	Exon 8 of 9	ENSP00000378292.2	Q6KB66-1
	KRT80	ENST00000313234.9	TSL:1	c.1182G>T	p.Met394Ile	missense	Exon 8 of 9	ENSP00000369361.2	Q6KB66-2
	KRT80	ENST00000466011.1	TSL:2	n.1338G>T		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.00000758 AC: 1 AN: 131918 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000660 AC: 1 AN: 151504 AF XY: 0.0000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 20 AN: 1035268 Hom.: 0 Cov.: 30 AF XY: 0.0000156 AC XY: 8 AN XY: 514026

African (AFR) AF: 0.00 AC: 0 AN: 23854

American (AMR) AF: 0.00 AC: 0 AN: 29292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18698

East Asian (EAS) AF: 0.00 AC: 0 AN: 26770

South Asian (SAS) AF: 0.00 AC: 0 AN: 69504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4520

European-Non Finnish (NFE) AF: 0.0000256 AC: 20 AN: 780514

Other (OTH) AF: 0.00 AC: 0 AN: 41660

GnomAD4 genome AF: 0.00000758 AC: 1 AN: 131918 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 63592

African (AFR) AF: 0.00 AC: 0 AN: 35000

American (AMR) AF: 0.00 AC: 0 AN: 12946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3184

East Asian (EAS) AF: 0.00 AC: 0 AN: 4360

South Asian (SAS) AF: 0.00 AC: 0 AN: 3686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000162 AC: 1 AN: 61700

Other (OTH) AF: 0.00 AC: 0 AN: 1844

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.0	L
PhyloP100		2.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.42
Sift	Benign	0.11	T
Sift4G	Benign	0.31	T
Polyphen		0.95	P
Vest4		0.44
MutPred		0.36		Gain of catalytic residue at R393 (P = 0.0211)
MVP		0.74
MPC		0.34
ClinPred		0.75	D
GERP RS		4.7
Varity_R		0.31
gMVP		0.50
Mutation Taster		=80/20	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: rs770804000; hg19: chr12-52565494;