12-52395007-C-G

Position:

• chr12-52395007-C-G

Variant summary

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

The NM_033033.4(KRT82):​c.1510G>C​(p.Ala504Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRT82 NM_033033.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.416

Genes affected

KRT82 (HGNC:6459): (keratin 82) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this keratin appears to be a hair cuticle-specific keratin. [provided by RefSeq, Jul 2008]

ENSG00000258253 (HGNC:):

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=0.095412016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT82	NM_033033.4	c.1510G>C	p.Ala504Pro	missense_variant	9/9	ENST00000257974.3	NP_149022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT82	ENST00000257974.3	c.1510G>C	p.Ala504Pro	missense_variant	9/9	1	NM_033033.4	ENSP00000257974.3
ENSG00000258253	ENST00000547174.1	n.147-6985C>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461484 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727082

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Nov 25, 2024

The c.1510G>C (p.A504P) alteration is located in exon 9 (coding exon 9) of the KRT82 gene. This alteration results from a G to C substitution at nucleotide position 1510, causing the alanine (A) at amino acid position 504 to be replaced by a proline (P). 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	0.082
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	3.1
DANN	Benign	0.96
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.40
Sift	Benign	0.043	D
Sift4G	Benign	0.23	T
Polyphen		0.61	P
Vest4		0.30
MutPred		0.12		Loss of catalytic residue at A504 (P = 0.0253);
MVP		0.42
MPC		0.099
ClinPred		0.086	T
GERP RS		-1.7
Varity_R		0.060
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: rs765996344; hg19: chr12-52788791;