rs114373469

Variant names:

• chr8-6499644-G-A
• rs114373469
• NM_001118887.2:c.*3457C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-6499644-G-A
• chr8-6499644-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001118887.2(ANGPT2):​c.*3457C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 517,064 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (3 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 8-6499644-G-A is Benign according to our data. Variant chr8-6499644-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1183190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.*3457C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2137-208G>A		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.*3457C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2137-208G>A		intron_variant	Intron 11 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 593 AN: 152008 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.000792 AC: 289 AN: 364938 Hom.: 3 Cov.: 3 AF XY: 0.000673 AC XY: 130 AN XY: 193180

African (AFR) AF: 0.0120 AC: 131 AN: 10890

American (AMR) AF: 0.00168 AC: 26 AN: 15474

Ashkenazi Jewish (ASJ) AF: 0.00645 AC: 73 AN: 11314

East Asian (EAS) AF: 0.0000391 AC: 1 AN: 25596

South Asian (SAS) AF: 0.0000818 AC: 3 AN: 36670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1592

European-Non Finnish (NFE) AF: 0.000141 AC: 31 AN: 220224

Other (OTH) AF: 0.00113 AC: 24 AN: 21152

GnomAD4 genome AF: 0.00390 AC: 593 AN: 152126 Hom.: 2 Cov.: 33 AF XY: 0.00394 AC XY: 293 AN XY: 74360

African (AFR) AF: 0.0118 AC: 490 AN: 41524

American (AMR) AF: 0.00301 AC: 46 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00483 Hom.: 1

Bravo AF: 0.00419

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 05, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.053
DANN	Benign	0.63
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

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: rs114373469; hg19: chr8-6357165;