12-52592461-C-T

Position:

• chr12-52592461-C-T

Variant summary

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

The NM_080747.3(KRT72):​c.733G>A​(p.Glu245Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRT72 NM_080747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

Genes affected

KRT72 (HGNC:28932): (keratin 72) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells. The type II keratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This gene encodes a type II keratin that is specifically expressed in the inner root sheath of hair follicles. The type II keratins are clustered in a region of chromosome 12q12-q13. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2009]

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, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT72	NM_080747.3	c.733G>A	p.Glu245Lys	missense_variant	4/9	ENST00000293745.7	NP_542785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT72	ENST00000293745.7	c.733G>A	p.Glu245Lys	missense_variant	4/9	1	NM_080747.3	ENSP00000293745	P1
KRT72	ENST00000537672.6	c.733G>A	p.Glu245Lys	missense_variant	4/10	2		ENSP00000441160	P1
KRT72	ENST00000354310.4	c.733G>A	p.Glu245Lys	missense_variant	4/8	2		ENSP00000346269
KRT72	ENST00000550829.1	c.*422G>A		3_prime_UTR_variant, NMD_transcript_variant	5/10	2		ENSP00000446881

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461774 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 03, 2022

The c.733G>A (p.E245K) alteration is located in exon 4 (coding exon 4) of the KRT72 gene. This alteration results from a G to A substitution at nucleotide position 733, causing the glutamic acid (E) at amino acid position 245 to be replaced by a lysine (K). 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	0.25
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H;H;H
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.64
MutPred		0.67		Gain of catalytic residue at M241 (P = 0.0442);Gain of catalytic residue at M241 (P = 0.0442);Gain of catalytic residue at M241 (P = 0.0442);
MVP		0.79
MPC		0.19
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.78
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1940072644; hg19: chr12-52986245;