12-52691432-C-A

Variant names:

• chr12-52691432-C-A
• rs1464619211
• NM_175078.3:c.1470G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_175078.3(KRT77):​c.1470G>T​(p.Gln490His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q490K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRT77 NM_175078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.682
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031787753).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT77	NM_175078.3	MANE Select	c.1470G>T	p.Gln490His	missense	Exon 9 of 9	NP_778253.2	Q7Z794

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT77	ENST00000341809.8	TSL:1 MANE Select	c.1470G>T	p.Gln490His	missense	Exon 9 of 9	ENSP00000342710.3	Q7Z794
	KRT77	ENST00000553168.1	TSL:1	n.*808G>T		non_coding_transcript_exon	Exon 10 of 10	ENSP00000448207.1	F8VS61
	KRT77	ENST00000553168.1	TSL:1	n.*808G>T		3_prime_UTR	Exon 10 of 10	ENSP00000448207.1	F8VS61

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000460 AC: 1 AN: 217354 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436242 Hom.: 0 Cov.: 43 AF XY: 0.00000140 AC XY: 1 AN XY: 713156

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33208

American (AMR) AF: 0.0000229 AC: 1 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.00 AC: 0 AN: 83128

European-Finnish (FIN) AF: 0.0000235 AC: 1 AN: 42476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104356

Other (OTH) AF: 0.00 AC: 0 AN: 59632

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.037	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.68
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.015
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Polyphen		0.0050	B
Vest4		0.14
MutPred		0.26		Loss of sheet (P = 3e-04)
MVP		0.20
MPC		0.18
ClinPred		0.049	T
GERP RS		-2.2
Varity_R		0.042
gMVP		0.27
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1464619211; hg19: chr12-53085216; COSMIC: COSV100527057; COSMIC: COSV100527057;