12-52171426-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011362284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT80	NM_182507.3	c.1331T>G	p.Phe444Cys	missense_variant	Exon 9 of 9	ENST00000394815.3	NP_872313.2
KRT80	XM_005268676.4	c.1436T>G	p.Phe479Cys	missense_variant	Exon 7 of 7		XP_005268733.1
KRT80	NM_001081492.2	c.*97T>G		3_prime_UTR_variant	Exon 9 of 9		NP_001074961.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT80	ENST00000394815.3	c.1331T>G	p.Phe444Cys	missense_variant	Exon 9 of 9	1	NM_182507.3	ENSP00000378292.2
KRT80	ENST00000313234	c.*97T>G		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000369361.2
KRT80	ENST00000466011.1	n.1487T>G		non_coding_transcript_exon_variant	Exon 7 of 7	2
LINC00592	ENST00000640420.1	n.413+6475A>C		intron_variant	Intron 2 of 2	5

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

GnomAD3 exomes AF: 0.000381 AC: 94 AN: 246778 Hom.: 1 AF XY: 0.000262 AC XY: 35 AN XY: 133398

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 SAS 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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000665

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000120 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1331T>G (p.F444C) alteration is located in exon 9 (coding exon 9) of the KRT80 gene. This alteration results from a T to G substitution at nucleotide position 1331, causing the phenylalanine (F) at amino acid position 444 to be replaced by a cysteine (C). 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	0.10
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
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

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

Other links and lift over

dbSNP: rs765254834; hg19: chr12-52565210;