NM_001118887.2:c.*3387T>A

Variant names:

• chr8-6499714-A-T
• rs2916716
• NM_001118887.2:c.*3387T>A

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.*3387T>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 0.287 in 723,324 control chromosomes in the GnomAD database, including 33,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5672 hom., cov: 32)
  • Exomes 𝑓: 0.30 (28164 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.137
• 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=-0.77).
• BP6: Variant 8-6499714-A-T is Benign according to our data. Variant chr8-6499714-A-T is described in ClinVar as Benign. ClinVar VariationId is 1262416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001118887.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPT2	NM_001118887.2	MANE Select	c.*3387T>A		3_prime_UTR	Exon 9 of 9	NP_001112359.1
	MCPH1	NM_024596.5	MANE Select	c.2137-138A>T		intron	N/A	NP_078872.3
	ANGPT2	NM_001147.3		c.*3387T>A		3_prime_UTR	Exon 9 of 9	NP_001138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.*3387T>A		3_prime_UTR	Exon 9 of 9	ENSP00000486858.2
	ANGPT2	ENST00000325203.9	TSL:1	c.*3387T>A		3_prime_UTR	Exon 9 of 9	ENSP00000314897.5
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2137-138A>T		intron	N/A	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36566 AN: 151974 Hom.: 5676 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.299 AC: 170966 AN: 571232 Hom.: 28164 Cov.: 7 AF XY: 0.299 AC XY: 91479 AN XY: 305510

African (AFR) AF: 0.0633 AC: 1048 AN: 16556

American (AMR) AF: 0.194 AC: 6519 AN: 33624

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 7534 AN: 19348

East Asian (EAS) AF: 0.0633 AC: 2157 AN: 34088

South Asian (SAS) AF: 0.240 AC: 14764 AN: 61644

European-Finnish (FIN) AF: 0.313 AC: 12147 AN: 38844

Middle Eastern (MID) AF: 0.363 AC: 873 AN: 2404

European-Non Finnish (NFE) AF: 0.349 AC: 116570 AN: 333972

Other (OTH) AF: 0.304 AC: 9354 AN: 30752

GnomAD4 genome AF: 0.240 AC: 36546 AN: 152092 Hom.: 5672 Cov.: 32 AF XY: 0.237 AC XY: 17596 AN XY: 74348

African (AFR) AF: 0.0597 AC: 2477 AN: 41510

American (AMR) AF: 0.223 AC: 3399 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1319 AN: 3470

East Asian (EAS) AF: 0.0630 AC: 326 AN: 5174

South Asian (SAS) AF: 0.208 AC: 1002 AN: 4820

European-Finnish (FIN) AF: 0.306 AC: 3227 AN: 10546

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

European-Non Finnish (NFE) AF: 0.351 AC: 23827 AN: 67978

Other (OTH) AF: 0.277 AC: 586 AN: 2116

Alfa AF: 0.280 Hom.: 836

Bravo AF: 0.228

Asia WGS AF: 0.140 AC: 487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.2
DANN	Benign	0.81
PhyloP100		-0.14
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: rs2916716; hg19: chr8-6357235;