8-6499750-C-T

Variant names:

• chr8-6499750-C-T
• rs115520116
• NM_001118887.2:c.*3351G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001118887.2(ANGPT2):​c.*3351G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 926,856 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (19 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (10 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.696
• Publications: 1 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=-0.89).
• BP6: Variant 8-6499750-C-T is Benign according to our data. Variant chr8-6499750-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1199699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00918 (1397/152224) while in subpopulation AFR AF = 0.0315 (1310/41526). AF 95% confidence interval is 0.0301. There are 19 homozygotes in GnomAd4. There are 641 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.*3351G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2137-102C>T		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.*3351G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2137-102C>T		intron_variant	Intron 11 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.00917 AC: 1395 AN: 152106 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00576

GnomAD4 exome AF: 0.00116 AC: 897 AN: 774632 Hom.: 10 Cov.: 10 AF XY: 0.000961 AC XY: 395 AN XY: 411208

African (AFR) AF: 0.0321 AC: 657 AN: 20476

American (AMR) AF: 0.00206 AC: 88 AN: 42702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21680

East Asian (EAS) AF: 0.00 AC: 0 AN: 36484

South Asian (SAS) AF: 0.0000279 AC: 2 AN: 71704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47116

Middle Eastern (MID) AF: 0.00250 AC: 7 AN: 2800

European-Non Finnish (NFE) AF: 0.0000851 AC: 42 AN: 493792

Other (OTH) AF: 0.00267 AC: 101 AN: 37878

GnomAD4 genome AF: 0.00918 AC: 1397 AN: 152224 Hom.: 19 Cov.: 33 AF XY: 0.00861 AC XY: 641 AN XY: 74430

African (AFR) AF: 0.0315 AC: 1310 AN: 41526

American (AMR) AF: 0.00425 AC: 65 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00570 AC: 12 AN: 2106

Alfa AF: 0.00871 Hom.: 3

Bravo AF: 0.0108

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 16, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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	-0.89
CADD	Benign	0.33
DANN	Benign	0.36
PhyloP100		-0.70
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: rs115520116; hg19: chr8-6357271;