chr12-52768725-G-T

Variant names:

• chr12-52768725-G-T
• rs1939128751
• NM_015848.4:c.1905C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015848.4(KRT76):​c.1905C>A​(p.Ser635Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRT76 NM_015848.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 0 publications found

Genes affected

KRT76 (HGNC:24430): (keratin 76) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. The type II keratins are clustered in a region of chromosome 12q13. [provided by RefSeq, Jun 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0779016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT76	NM_015848.4	c.1905C>A	p.Ser635Arg	missense_variant	Exon 9 of 9	ENST00000332411.2	NP_056932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT76	ENST00000332411.2	c.1905C>A	p.Ser635Arg	missense_variant	Exon 9 of 9	1	NM_015848.4	ENSP00000330101.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442440 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 713210

⚠️ 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: 33196

American (AMR) AF: 0.00 AC: 0 AN: 44298

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 39124

South Asian (SAS) AF: 0.00 AC: 0 AN: 85222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096790

Other (OTH) AF: 0.00 AC: 0 AN: 59442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000474 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.55
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.28		Loss of phosphorylation at S635 (P = 0.0038);
MVP		0.37
MPC		0.055
ClinPred		0.033	T
GERP RS		3.7
Varity_R		0.066
gMVP		0.40
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1939128751; hg19: chr12-53162509;