rs12339582

chr9-35398903-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001371189.2(UNC13B):c.11943G>T(p.Glu3981Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,614,082 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.026 (182 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (161 hom.)
• Consequence: UNC13B NM_001371189.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0430

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026662648).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13B	NM_001371189.2	c.11943G>T	p.Glu3981Asp	missense_variant	33/40	ENST00000635942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13B	ENST00000635942.2	c.11943G>T	p.Glu3981Asp	missense_variant	33/40	5	NM_001371189.2

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3927 AN: 152146 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00779 AC: 1956 AN: 251246 Hom.: 70 AF XY: 0.00579 AC XY: 786 AN XY: 135778

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0154

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00331 AC: 4836 AN: 1461818 Hom.: 161 Cov.: 32 AF XY: 0.00299 AC XY: 2175 AN XY: 727208

Gnomad4 AFR exome AF: 0.0910

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0178

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000380

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.0259 AC: 3940 AN: 152264 Hom.: 182 Cov.: 32 AF XY: 0.0249 AC XY: 1856 AN XY: 74452

Gnomad4 AFR AF: 0.0879

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0128

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00550 Hom.: 48

Bravo AF: 0.0292

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0860 AC: 379

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00940 AC: 1141

Asia WGS AF: 0.0140 AC: 52 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0027	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.45	T;T;T;.;T;T;.;T
Polyphen		0.011	.;.;.;.;B;.;.;.
Vest4		0.23
MutPred		0.50		Loss of helix (P = 0.0558);.;.;.;Loss of helix (P = 0.0558);.;.;.;
MVP		0.33
MPC		0.19
ClinPred		0.013	T
GERP RS		4.1
Varity_R		0.25
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs12339582; hg19: chr9-35398900;