rs2916715

Variant names:

• chr8-6499786-T-C
• rs2916715
• NM_001118887.2:c.*3315A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-6499786-T-C
• chr8-6499786-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001118887.2(ANGPT2):​c.*3315A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,429,614 control chromosomes in the GnomAD database, including 78,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5822 hom., cov: 32)
  • Exomes 𝑓: 0.33 (72797 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.210
• Publications: 9 publications found

Genes affected

ANGPT2 (HGNC:485): (angiopoietin 2) This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MCPH1 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-6499786-T-C is Benign according to our data. Variant chr8-6499786-T-C is described in ClinVar as [Benign]. Clinvar id is 1175465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.*3315A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2137-66T>C		intron_variant	Intron 11 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT2	ENST00000629816.3	c.*3315A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2137-66T>C		intron_variant	Intron 11 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37238 AN: 151986 Hom.: 5826 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.329 AC: 419770 AN: 1277512 Hom.: 72797 Cov.: 18 AF XY: 0.329 AC XY: 212542 AN XY: 645428

African (AFR) AF: 0.0568 AC: 1688 AN: 29738

American (AMR) AF: 0.191 AC: 8485 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 9763 AN: 24946

East Asian (EAS) AF: 0.0869 AC: 3370 AN: 38778

South Asian (SAS) AF: 0.283 AC: 23377 AN: 82490

European-Finnish (FIN) AF: 0.311 AC: 16299 AN: 52378

Middle Eastern (MID) AF: 0.374 AC: 1428 AN: 3816

European-Non Finnish (NFE) AF: 0.358 AC: 338583 AN: 946816

Other (OTH) AF: 0.310 AC: 16777 AN: 54092

GnomAD4 genome AF: 0.245 AC: 37220 AN: 152102 Hom.: 5822 Cov.: 32 AF XY: 0.242 AC XY: 17967 AN XY: 74370

African (AFR) AF: 0.0615 AC: 2555 AN: 41536

American (AMR) AF: 0.222 AC: 3400 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1324 AN: 3466

East Asian (EAS) AF: 0.0933 AC: 483 AN: 5178

South Asian (SAS) AF: 0.260 AC: 1250 AN: 4812

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

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23993 AN: 67956

Other (OTH) AF: 0.281 AC: 591 AN: 2106

Alfa AF: 0.199 Hom.: 638

Bravo AF: 0.232

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

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	-0.79
CADD	Benign	2.1
DANN	Benign	0.81
PhyloP100		-0.21
Mutation Taster		=98/2	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: rs2916715; hg19: chr8-6357307;