9-35398903-G-T

Variant names:

• chr9-35398903-G-T
• rs12339582
• NM_001371189.2:c.11943G>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371189.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13B	NM_001371189.2	MANE Select	c.11943G>T	p.Glu3981Asp	missense	Exon 33 of 40	NP_001358118.1	A0A1B0GUS7
	UNC13B	NM_001371187.2		c.4836G>T	p.Glu1612Asp	missense	Exon 25 of 33	NP_001358116.1	A0A1B0GVW8
	UNC13B	NM_001387555.1		c.4833G>T	p.Glu1611Asp	missense	Exon 25 of 33	NP_001374484.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13B	ENST00000635942.2	TSL:5 MANE Select	c.11943G>T	p.Glu3981Asp	missense	Exon 33 of 40	ENSP00000490228.1	A0A1B0GUS7
	UNC13B	ENST00000619578.4	TSL:1	c.3696G>T	p.Glu1232Asp	missense	Exon 32 of 40	ENSP00000479261.1	O14795-2
	UNC13B	ENST00000378495.7	TSL:1	c.3696G>T	p.Glu1232Asp	missense	Exon 32 of 39	ENSP00000367756.3	O14795-1

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

GnomAD2 exomes AF: 0.00779 AC: 1956 AN: 251246 AF XY: 0.00579

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 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

African (AFR) AF: 0.0910 AC: 3046 AN: 33476

American (AMR) AF: 0.00474 AC: 212 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0178 AC: 705 AN: 39700

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000380 AC: 423 AN: 1111976

Other (OTH) AF: 0.00601 AC: 363 AN: 60392

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

African (AFR) AF: 0.0879 AC: 3651 AN: 41540

American (AMR) AF: 0.0101 AC: 154 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0128 AC: 66 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.00781 Hom.: 106

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 v4.9

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
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.043
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Benign	0.34	T
Sift4G	Benign	0.45	T
Polyphen		0.011	B
Vest4		0.23
MutPred		0.50		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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12339582; hg19: chr9-35398900;