9-35295883-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001371189.2(UNC13B):c.714C>A(p.Asp238Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00943 in 1,613,968 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (124 hom.)
• Consequence: UNC13B NM_001371189.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.82

Genes affected

UNC13B (HGNC:12566): (unc-13 homolog B) This gene is expressed in the kidney cortical epithelial cells and is upregulated by hyperglycemia. The encoded protein shares a high level of similarity to the rat homolog, and contains 3 C2 domains and a diacylglycerol-binding C1 domain. Hyperglycemia increases the levels of diacylglycerol, which has been shown to induce apoptosis in cells transfected with this gene and thus contribute to the renal cell complications of hyperglycemia. Studies in other species also indicate a role for this protein in the priming step of synaptic vesicle exocytosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052330196).
• BP6: Variant 9-35295883-C-A is Benign according to our data. Variant chr9-35295883-C-A is described in ClinVar as [Benign]. Clinvar id is 774465.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00961 (14047/1461696) while in subpopulation MID AF= 0.0333 (192/5768). AF 95% confidence interval is 0.0294. There are 124 homozygotes in gnomad4_exome. There are 7017 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13B	NM_001371189.2	c.714C>A	p.Asp238Glu	missense_variant	8/40	ENST00000635942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13B	ENST00000635942.2	c.714C>A	p.Asp238Glu	missense_variant	8/40	5	NM_001371189.2

Frequencies

GnomAD3 genomes AF: 0.00768 AC: 1168 AN: 152154 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00994

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00892 AC: 2238 AN: 250888 Hom.: 23 AF XY: 0.00881 AC XY: 1194 AN XY: 135588

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00896

Gnomad ASJ exome AF: 0.0498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.00961 AC: 14047 AN: 1461696 Hom.: 124 Cov.: 31 AF XY: 0.00965 AC XY: 7017 AN XY: 727110

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0514

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00399

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00971

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.00766 AC: 1167 AN: 152272 Hom.: 7 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74450

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0521

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00994

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0121 Hom.: 29

Bravo AF: 0.00925

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0144 AC: 124

ExAC AF: 0.00784 AC: 952

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0156

EpiControl AF: 0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D
MetaRNN	Benign	0.0052	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.4	M;.;.;M
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.17	T;T;.;T
Polyphen		0.88	.;.;.;P
Vest4		0.59
MutPred		0.15		Gain of catalytic residue at D238 (P = 0.1575);.;Gain of catalytic residue at D238 (P = 0.1575);Gain of catalytic residue at D238 (P = 0.1575);
MVP		0.66
MPC		0.26
ClinPred		0.036	T
GERP RS		2.0
Varity_R		0.087
gMVP		0.19

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: rs35199210; hg19: chr9-35295880; COSMIC: COSV101037603;