12-52839944-C-T

Position:

• chr12-52839944-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173352.4(KRT78):​c.1088G>A​(p.Arg363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,613,964 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (39 hom.)
• Consequence: KRT78 NM_173352.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0900

Genes affected

KRT78 (HGNC:28926): (keratin 78) This gene is a member of the type II keratin gene family and encodes a protein with an intermediate filament domain. Keratins are the major structural proteins in epithelial cells, forming a cytoplasmic network of 10 to 12 nm wide intermediate filaments and creating a scaffold that gives cells the ability to withstand mechanical and non-mechanical stresses. The genes of the type II keratin family are located as a gene cluster at 12p13.13. Four pseudogenes of this gene family have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077881515).
• BP6: Variant 12-52839944-C-T is Benign according to our data. Variant chr12-52839944-C-T is described in ClinVar as [Benign]. Clinvar id is 785409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1756/152186) while in subpopulation AFR AF= 0.0395 (1638/41494). AF 95% confidence interval is 0.0379. There are 34 homozygotes in gnomad4. There are 805 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT78	NM_173352.4	c.1088G>A	p.Arg363His	missense_variant	7/9	ENST00000304620.5	NP_775487.2
KRT78	NM_001300814.1	c.758G>A	p.Arg253His	missense_variant	7/9		NP_001287743.1
KRT78	XM_011538010.2	c.992G>A	p.Arg331His	missense_variant	6/8		XP_011536312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT78	ENST00000304620.5	c.1088G>A	p.Arg363His	missense_variant	7/9	1	NM_173352.4	ENSP00000306261.4
KRT78	ENST00000359499.8	c.758G>A	p.Arg253His	missense_variant	7/9	1		ENSP00000352479.4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1755 AN: 152068 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00351 AC: 882 AN: 251192 Hom.: 12 AF XY: 0.00252 AC XY: 342 AN XY: 135798

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00266

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00143 AC: 2092 AN: 1461778 Hom.: 39 Cov.: 31 AF XY: 0.00121 AC XY: 882 AN XY: 727178

Gnomad4 AFR exome AF: 0.0421

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00259

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.0115 AC: 1756 AN: 152186 Hom.: 34 Cov.: 32 AF XY: 0.0108 AC XY: 805 AN XY: 74400

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00515 Hom.: 7

Bravo AF: 0.0140

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0413 AC: 182

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00413 AC: 501

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.27
Sift	Benign	0.084	T;T
Sift4G	Benign	0.079	T;T
Polyphen		0.083	.;B
Vest4		0.24
MVP		0.30
MPC		0.047
ClinPred		0.0096	T
GERP RS		0.11
Varity_R		0.064
gMVP		0.041

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: rs77199066; hg19: chr12-53233728;