12-52173066-C-G

Variant names:

• chr12-52173066-C-G
• NM_182507.3:c.929G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182507.3(KRT80):​c.929G>C​(p.Arg310Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R310Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT80 NM_182507.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT80	NM_182507.3	c.929G>C	p.Arg310Pro	missense_variant	Exon 6 of 9	ENST00000394815.3	NP_872313.2
KRT80	NM_001081492.2	c.929G>C	p.Arg310Pro	missense_variant	Exon 6 of 9		NP_001074961.1
KRT80	XM_005268676.4	c.1034G>C	p.Arg345Pro	missense_variant	Exon 4 of 7		XP_005268733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT80	ENST00000394815.3	c.929G>C	p.Arg310Pro	missense_variant	Exon 6 of 9	1	NM_182507.3	ENSP00000378292.2
KRT80	ENST00000313234.9	c.929G>C	p.Arg310Pro	missense_variant	Exon 6 of 9	1		ENSP00000369361.2
KRT80	ENST00000466011.1	n.1085G>C		non_coding_transcript_exon_variant	Exon 4 of 7	2
LINC00592	ENST00000640420.1	n.413+8115C>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460386 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726324

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.61		Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);
MVP		0.67
MPC		0.65
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52566850;