12-52691272-C-A

Variant summary

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

The NM_175078.3(KRT77):c.1630G>T(p.Gly544Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,446,060 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRT77 NM_175078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.79

Genes affected

KRT77 (HGNC:20411): (keratin 77) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This gene encodes an epithelial keratin that is expressed in the skin and eccrine sweat glands. The type II keratins are clustered in a region of chromosome 12q13.[provided by RefSeq, Jun 2009]

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=0.23111501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT77	NM_175078.3	c.1630G>T	p.Gly544Cys	missense_variant	9/9	ENST00000341809.8
KRT77	XM_011538288.3	c.931G>T	p.Gly311Cys	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT77	ENST00000341809.8	c.1630G>T	p.Gly544Cys	missense_variant	9/9	1	NM_175078.3	P1
KRT77	ENST00000553168.1	c.*968G>T		3_prime_UTR_variant, NMD_transcript_variant	10/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446060 Hom.: 0 Cov.: 62 AF XY: 0.00000139 AC XY: 1 AN XY: 718712

Gnomad4 AFR exome AF: 0.0000302

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.: 32

Bravo AF: 0.00000378

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 26, 2023

The c.1630G>T (p.G544C) alteration is located in exon 9 (coding exon 9) of the KRT77 gene. This alteration results from a G to T substitution at nucleotide position 1630, causing the glycine (G) at amino acid position 544 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	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	7.2
Dann	Benign	0.89
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.59	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.033	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.38		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.68
MPC		0.20
ClinPred		0.66	D
GERP RS		0.046
Varity_R		0.18
gMVP		0.66

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: rs1941701152; hg19: chr12-53085056;