chr12-52245451-C-T

Position:

• chr12-52245451-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005556.4(KRT7):​c.1024C>T​(p.Arg342Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,962 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: KRT7 NM_005556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

Genes affected

KRT7 (HGNC:6445): (keratin 7) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins 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 type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

KRT7-AS (HGNC:52643): (KRT7 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0520325).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT7	NM_005556.4	c.1024C>T	p.Arg342Cys	missense_variant	7/9	ENST00000331817.6
KRT7-AS	NR_146274.1	n.1290G>A		non_coding_transcript_exon_variant	2/2
KRT7	XM_011538325.3	c.1024C>T	p.Arg342Cys	missense_variant	7/8
KRT7	XM_017019294.2	c.493C>T	p.Arg165Cys	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT7	ENST00000331817.6	c.1024C>T	p.Arg342Cys	missense_variant	7/9	1	NM_005556.4	P1
KRT7-AS	ENST00000546686.1	n.1290G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152214 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000687 AC: 172 AN: 250462 Hom.: 2 AF XY: 0.000745 AC XY: 101 AN XY: 135532

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00103 AC: 1510 AN: 1461630 Hom.: 4 Cov.: 30 AF XY: 0.000970 AC XY: 705 AN XY: 727136

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152332 Hom.: 0 Cov.: 34 AF XY: 0.000685 AC XY: 51 AN XY: 74486

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000759

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000436

EpiControl AF: 0.000830

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

Jul 14, 2021

The c.1024C>T (p.R342C) alteration is located in exon 7 (coding exon 7) of the KRT7 gene. This alteration results from a C to T substitution at nucleotide position 1024, causing the arginine (R) at amino acid position 342 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.046
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.052	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.065	T
Polyphen		0.82	P
Vest4		0.40
MVP		0.73
MPC		0.38
ClinPred		0.22	T
GERP RS		3.5
Varity_R		0.42
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1046362; hg19: chr12-52639235;