rs2290768

Variant names:

• chr17-75830530-G-A
• rs2290768
• NM_199242.3:c.2709+48C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75830530-G-A
• chr17-75830530-G-T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -2.23
• Publications: 9 publications found

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]

UNC13D Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.2709+48C>T		intron_variant	Intron 28 of 31	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.2709+48C>T		intron_variant	Intron 28 of 31	1	NM_199242.3	ENSP00000207549.3

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

GnomAD2 exomes AF: 0.135 AC: 25453 AN: 188306 AF XY: 0.132

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 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

African (AFR) AF: 0.424 AC: 13912 AN: 32794

American (AMR) AF: 0.110 AC: 4267 AN: 38922

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4104 AN: 25456

East Asian (EAS) AF: 0.327 AC: 12394 AN: 37878

South Asian (SAS) AF: 0.153 AC: 12463 AN: 81580

European-Finnish (FIN) AF: 0.0552 AC: 2768 AN: 50186

Middle Eastern (MID) AF: 0.256 AC: 1448 AN: 5656

European-Non Finnish (NFE) AF: 0.0657 AC: 71814 AN: 1093314

Other (OTH) AF: 0.120 AC: 7083 AN: 58958

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

African (AFR) AF: 0.413 AC: 17136 AN: 41490

American (AMR) AF: 0.114 AC: 1742 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 616 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1588 AN: 5152

South Asian (SAS) AF: 0.150 AC: 723 AN: 4832

European-Finnish (FIN) AF: 0.0543 AC: 576 AN: 10616

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.0716 AC: 4871 AN: 68004

Other (OTH) AF: 0.172 AC: 364 AN: 2116

Alfa AF: 0.146 Hom.: 742

Bravo AF: 0.199

Asia WGS AF: 0.219 AC: 763 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.061
DANN	Benign	0.58
PhyloP100		-2.2
PromoterAI		0.076	Neutral
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: rs2290768; hg19: chr17-73826611; COSMIC: COSV52884252; COSMIC: COSV52884252;