NM_001118887.2:c.*3415T>C

Variant names:

• chr8-6499686-A-G
• rs2442474
• NM_001118887.2:c.*3415T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001118887.2(ANGPT2):​c.*3415T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 627,316 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.016 (70 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0430
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-6499686-A-G is Benign according to our data. Variant chr8-6499686-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1187061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1995/152326) while in subpopulation NFE AF = 0.019 (1291/68024). AF 95% confidence interval is 0.0181. There are 24 homozygotes in GnomAd4. There are 945 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.*3415T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2137-166A>G		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.*3415T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2137-166A>G		intron_variant	Intron 11 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1994 AN: 152208 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0201

GnomAD4 exome AF: 0.0156 AC: 7407 AN: 474990 Hom.: 70 Cov.: 5 AF XY: 0.0148 AC XY: 3735 AN XY: 252628

African (AFR) AF: 0.00309 AC: 41 AN: 13252

American (AMR) AF: 0.0108 AC: 249 AN: 22958

Ashkenazi Jewish (ASJ) AF: 0.00821 AC: 128 AN: 15586

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30838

South Asian (SAS) AF: 0.00110 AC: 54 AN: 48888

European-Finnish (FIN) AF: 0.0327 AC: 1045 AN: 31950

Middle Eastern (MID) AF: 0.00194 AC: 4 AN: 2062

European-Non Finnish (NFE) AF: 0.0193 AC: 5467 AN: 282604

Other (OTH) AF: 0.0156 AC: 418 AN: 26852

GnomAD4 genome AF: 0.0131 AC: 1995 AN: 152326 Hom.: 24 Cov.: 33 AF XY: 0.0127 AC XY: 945 AN XY: 74484

African (AFR) AF: 0.00356 AC: 148 AN: 41578

American (AMR) AF: 0.0107 AC: 164 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.0300 AC: 318 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0190 AC: 1291 AN: 68024

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0156 Hom.: 6

Bravo AF: 0.0113

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: Likely 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	-0.89
CADD	Benign	0.90
DANN	Benign	0.63
PhyloP100		-0.043
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: rs2442474; hg19: chr8-6357207;