rs1941951599

Variant names:

• chr12-52233427-C-G
• rs1941951599
• NM_005556.4:c.131C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005556.4(KRT7):​c.131C>G​(p.Ala44Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT7 NM_005556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039885014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT7	NM_005556.4	c.131C>G	p.Ala44Gly	missense_variant	Exon 1 of 9	ENST00000331817.6	NP_005547.3
KRT7	XM_011538325.3	c.131C>G	p.Ala44Gly	missense_variant	Exon 1 of 8		XP_011536627.1
KRT7	XM_047428827.1	c.131C>G	p.Ala44Gly	missense_variant	Exon 1 of 7		XP_047284783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT7	ENST00000331817.6	c.131C>G	p.Ala44Gly	missense_variant	Exon 1 of 9	1	NM_005556.4	ENSP00000329243.5
KRT7	ENST00000546666.1	n.279C>G		non_coding_transcript_exon_variant	Exon 2 of 2	4
KRT7	ENST00000547613.1	n.-165C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405972 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698452

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: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131C>G (p.A44G) alteration is located in exon 1 (coding exon 1) of the KRT7 gene. This alteration results from a C to G substitution at nucleotide position 131, causing the alanine (A) at amino acid position 44 to be replaced by a glycine (G). 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	0.072
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.071	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.40	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.22
Sift	Benign	0.62	T
Sift4G	Benign	1.0	T
Polyphen		0.10	B
Vest4		0.13
MutPred		0.29		Loss of MoRF binding (P = 0.1121);
MVP		0.31
MPC		0.41
ClinPred		0.17	T
GERP RS		4.5
Varity_R		0.058
gMVP		0.46

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: rs1941951599; hg19: chr12-52627211;