12-52172201-C-T

Variant names:

• chr12-52172201-C-T
• rs371482488
• NM_182507.3:c.1175G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182507.3(KRT80):​c.1175G>A​(p.Gly392Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT80 NM_182507.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.563

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.095629305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT80	NM_182507.3	c.1175G>A	p.Gly392Asp	missense_variant	Exon 7 of 9	ENST00000394815.3	NP_872313.2
KRT80	NM_001081492.2	c.1175G>A	p.Gly392Asp	missense_variant	Exon 7 of 9		NP_001074961.1
KRT80	XM_005268676.4	c.1280G>A	p.Gly427Asp	missense_variant	Exon 5 of 7		XP_005268733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT80	ENST00000394815.3	c.1175G>A	p.Gly392Asp	missense_variant	Exon 7 of 9	1	NM_182507.3	ENSP00000378292.2
KRT80	ENST00000313234.9	c.1175G>A	p.Gly392Asp	missense_variant	Exon 7 of 9	1		ENSP00000369361.2
KRT80	ENST00000466011.1	n.1331G>A		non_coding_transcript_exon_variant	Exon 5 of 7	2
LINC00592	ENST00000640420.1	n.413+7250C>T		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461026 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1175G>A (p.G392D) alteration is located in exon 7 (coding exon 7) of the KRT80 gene. This alteration results from a G to A substitution at nucleotide position 1175, causing the glycine (G) at amino acid position 392 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.094	.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	-0.14	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.13
Sift	Benign	0.23	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0010	B;B
Vest4		0.12
MVP		0.45
MPC		0.17
ClinPred		0.38	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.27

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: rs371482488; hg19: chr12-52565985;