12-52171522-G-A

Position:

• chr12-52171522-G-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.1235C>T​(p.Ala412Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT80 NM_182507.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.804

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=0.085253805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT80	NM_182507.3	c.1235C>T	p.Ala412Val	missense_variant, splice_region_variant	9/9	ENST00000394815.3	NP_872313.2
KRT80	XM_005268676.4	c.1340C>T	p.Ala447Val	missense_variant, splice_region_variant	7/7		XP_005268733.1
KRT80	NM_001081492.2	c.*1C>T		3_prime_UTR_variant	9/9		NP_001074961.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT80	ENST00000394815.3	c.1235C>T	p.Ala412Val	missense_variant, splice_region_variant	9/9	1	NM_182507.3	ENSP00000378292	P1
KRT80	ENST00000313234.9	c.*1C>T		3_prime_UTR_variant	9/9	1		ENSP00000369361
LINC00592	ENST00000640420.1	n.413+6571G>A		intron_variant, non_coding_transcript_variant		5
KRT80	ENST00000466011.1	n.1391C>T		splice_region_variant, non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.1235C>T (p.A412V) alteration is located in exon 9 (coding exon 9) of the KRT80 gene. This alteration results from a C to T substitution at nucleotide position 1235, causing the alanine (A) at amino acid position 412 to be replaced by a valine (V). 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	0.084
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.46	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.24		Gain of catalytic residue at S416 (P = 0.001);
MVP		0.44
MPC		0.11
ClinPred		0.24	T
GERP RS		1.6
Varity_R		0.044
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52565306;