12-52241520-T-C

Position:

• chr12-52241520-T-C

Variant summary

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

The NM_005556.4(KRT7):​c.742T>C​(p.Ser248Pro) 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 1,461,652 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: 0.0000021 (0 hom.)
• Consequence: KRT7 NM_005556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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]

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, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT7	NM_005556.4	c.742T>C	p.Ser248Pro	missense_variant	5/9	ENST00000331817.6	NP_005547.3
KRT7	XM_011538325.3	c.742T>C	p.Ser248Pro	missense_variant	5/8		XP_011536627.1
KRT7	XM_047428827.1	c.742T>C	p.Ser248Pro	missense_variant	5/7		XP_047284783.1
KRT7	XM_017019294.2	c.211T>C	p.Ser71Pro	missense_variant	3/7		XP_016874783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT7	ENST00000331817.6	c.742T>C	p.Ser248Pro	missense_variant	5/9	1	NM_005556.4	ENSP00000329243	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461652 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727158

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.: 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

Dec 01, 2022

The c.742T>C (p.S248P) alteration is located in exon 5 (coding exon 5) of the KRT7 gene. This alteration results from a T to C substitution at nucleotide position 742, causing the serine (S) at amino acid position 248 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	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.33	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.3	D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.022	D;.
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.63		Loss of phosphorylation at S248 (P = 0.0501);.;
MVP		0.59
MPC		1.1
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.84
gMVP		0.62

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: chr12-52635304;