chr9-35381507-C-T

Variant names:

• chr9-35381507-C-T
• rs2281999
• NM_001371189.2:c.10492-49C>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.10492-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,554,452 control chromosomes in the GnomAD database, including 90,491 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (11805 hom., cov: 32)
  • Exomes 𝑓: 0.33 (78686 hom.)
• Consequence: UNC13B NM_001371189.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437
• 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 (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.522 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13B	NM_001371189.2	MANE Select	c.10492-49C>T		intron	N/A	NP_001358118.1
	UNC13B	NM_001371187.2		c.3385-49C>T		intron	N/A	NP_001358116.1
	UNC13B	NM_001387555.1		c.3385-49C>T		intron	N/A	NP_001374484.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13B	ENST00000635942.2	TSL:5 MANE Select	c.10492-49C>T		intron	N/A	ENSP00000490228.1
	UNC13B	ENST00000619578.4	TSL:1	c.2245-49C>T		intron	N/A	ENSP00000479261.1
	UNC13B	ENST00000378495.7	TSL:1	c.2245-49C>T		intron	N/A	ENSP00000367756.3

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57657 AN: 151888 Hom.: 11767 Cov.: 32

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.346 AC: 72214 AN: 208824 AF XY: 0.347

Gnomad AFR exome AF: 0.531

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.331 AC: 463562 AN: 1402448 Hom.: 78686 Cov.: 31 AF XY: 0.333 AC XY: 230162 AN XY: 691404

African (AFR) AF: 0.533 AC: 16657 AN: 31224

American (AMR) AF: 0.286 AC: 10120 AN: 35350

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6045 AN: 23000

East Asian (EAS) AF: 0.424 AC: 16540 AN: 38996

South Asian (SAS) AF: 0.451 AC: 35273 AN: 78244

European-Finnish (FIN) AF: 0.309 AC: 15907 AN: 51526

Middle Eastern (MID) AF: 0.258 AC: 1417 AN: 5492

European-Non Finnish (NFE) AF: 0.316 AC: 341904 AN: 1081022

Other (OTH) AF: 0.342 AC: 19699 AN: 57594

GnomAD4 genome AF: 0.380 AC: 57742 AN: 152004 Hom.: 11805 Cov.: 32 AF XY: 0.379 AC XY: 28164 AN XY: 74286

African (AFR) AF: 0.528 AC: 21889 AN: 41442

American (AMR) AF: 0.310 AC: 4729 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 906 AN: 3464

East Asian (EAS) AF: 0.447 AC: 2307 AN: 5166

South Asian (SAS) AF: 0.452 AC: 2176 AN: 4816

European-Finnish (FIN) AF: 0.307 AC: 3240 AN: 10558

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21449 AN: 67968

Other (OTH) AF: 0.351 AC: 741 AN: 2112

Alfa AF: 0.328 Hom.: 10932

Bravo AF: 0.382

Asia WGS AF: 0.422 AC: 1468 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.73
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

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: rs2281999; hg19: chr9-35381504; COSMIC: COSV107492307;