12-52768760-G-A

Variant names:

• chr12-52768760-G-A
• rs140818538
• NM_015848.4:c.1870C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015848.4(KRT76):​c.1870C>T​(p.Arg624Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,610,622 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: KRT76 NM_015848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042551875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT76	NM_015848.4	c.1870C>T	p.Arg624Cys	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.1870C>T	p.Arg624Cys	missense_variant	Exon 9 of 9	1	NM_015848.4	ENSP00000330101.2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251222 AF XY: 0.000162

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1458374 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 98 AN XY: 724694

African (AFR) AF: 0.000419 AC: 14 AN: 33414

American (AMR) AF: 0.000605 AC: 27 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000144 AC: 160 AN: 1109176

Other (OTH) AF: 0.000199 AC: 12 AN: 60190

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152248 Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 24 AN XY: 74452

African (AFR) AF: 0.000674 AC: 28 AN: 41540

American (AMR) AF: 0.000981 AC: 15 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1870C>T (p.R624C) alteration is located in exon 9 (coding exon 9) of the KRT76 gene. This alteration results from a C to T substitution at nucleotide position 1870, causing the arginine (R) at amino acid position 624 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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.043	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.17
MVP		0.67
MPC		0.064
ClinPred		0.023	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.48
Mutation Taster		=89/11	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: rs140818538; hg19: chr12-53162544; COSMIC: COSV60121344; COSMIC: COSV60121344;