rs2290768

chr17-75830530-G-Achr17-75830530-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):c.2709+48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,576,936 control chromosomes in the GnomAD database, including 14,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4281 hom., cov: 33)
  • Exomes 𝑓: 0.091 (10053 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.23

Genes affected

UNC13D (HGNC:23147): (unc-13 homolog D) This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-75830530-G-A is Benign according to our data. Variant chr17-75830530-G-A is described in ClinVar as [Benign]. Clinvar id is 263233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.2709+48C>T		intron_variant		ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.2709+48C>T		intron_variant		1	NM_199242.3	P1
UNC13D	ENST00000412096.6	c.2709+48C>T		intron_variant		2
UNC13D	ENST00000699510.1	c.1575+48C>T		intron_variant
UNC13D	ENST00000590856.1	n.84+48C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27635 AN: 152074 Hom.: 4253 Cov.: 33

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0543

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.135 AC: 25453 AN: 188306 Hom.: 2688 AF XY: 0.132 AC XY: 13323 AN XY: 100700

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.315

Gnomad SAS exome AF: 0.159

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.0750

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.0914 AC: 130253 AN: 1424744 Hom.: 10053 Cov.: 34 AF XY: 0.0930 AC XY: 65568 AN XY: 705264

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.327

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.0552

Gnomad4 NFE exome AF: 0.0657

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.182 AC: 27703 AN: 152192 Hom.: 4281 Cov.: 33 AF XY: 0.181 AC XY: 13435 AN XY: 74430

Gnomad4 AFR AF: 0.413

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0543

Gnomad4 NFE AF: 0.0716

Gnomad4 OTH AF: 0.172

Alfa AF: 0.136 Hom.: 621

Bravo AF: 0.199

Asia WGS AF: 0.219 AC: 763 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.061
Dann	Benign	0.58

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: rs2290768; hg19: chr17-73826611; COSMIC: COSV52884252; COSMIC: COSV52884252;