chr8-6562969-C-G

Variant names:

• chr8-6562969-C-G
• rs3739390
• NM_001118887.2:c.-35G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001118887.2(ANGPT2):​c.-35G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,550,278 control chromosomes in the GnomAD database, including 3,146 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.060 (333 hom., cov: 29)
  • Exomes 𝑓: 0.061 (2813 hom.)
• Consequence: ANGPT2 NM_001118887.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 22 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 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.-35G>C		5_prime_UTR	Exon 1 of 9	NP_001112359.1
	MCPH1	NM_024596.5	MANE Select	c.2215-58485C>G		intron	N/A	NP_078872.3
	ANGPT2	NM_001147.3		c.-35G>C		5_prime_UTR	Exon 1 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.-35G>C		5_prime_UTR	Exon 1 of 9	ENSP00000486858.2
	ANGPT2	ENST00000325203.9	TSL:1	c.-35G>C		5_prime_UTR	Exon 1 of 9	ENSP00000314897.5
	ANGPT2	ENST00000523120.2	TSL:1	c.-35G>C		5_prime_UTR	Exon 1 of 8	ENSP00000428023.1

Frequencies

GnomAD3 genomes AF: 0.0604 AC: 9189 AN: 152132 Hom.: 332 Cov.: 29

Gnomad AFR AF: 0.0536

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0687

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0845

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0668 AC: 14512 AN: 217262 AF XY: 0.0676

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.0718

Gnomad ASJ exome AF: 0.0928

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0535

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0613 AC: 85672 AN: 1398028 Hom.: 2813 Cov.: 32 AF XY: 0.0620 AC XY: 42528 AN XY: 685772

African (AFR) AF: 0.0581 AC: 1883 AN: 32386

American (AMR) AF: 0.0695 AC: 2917 AN: 41956

Ashkenazi Jewish (ASJ) AF: 0.0877 AC: 2006 AN: 22868

East Asian (EAS) AF: 0.104 AC: 4033 AN: 38766

South Asian (SAS) AF: 0.0912 AC: 6992 AN: 76644

European-Finnish (FIN) AF: 0.0448 AC: 2245 AN: 50130

Middle Eastern (MID) AF: 0.0773 AC: 412 AN: 5328

European-Non Finnish (NFE) AF: 0.0571 AC: 61252 AN: 1072386

Other (OTH) AF: 0.0683 AC: 3932 AN: 57564

GnomAD4 genome AF: 0.0604 AC: 9198 AN: 152250 Hom.: 333 Cov.: 29 AF XY: 0.0615 AC XY: 4580 AN XY: 74440

African (AFR) AF: 0.0535 AC: 2223 AN: 41552

American (AMR) AF: 0.0690 AC: 1056 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

East Asian (EAS) AF: 0.121 AC: 627 AN: 5166

South Asian (SAS) AF: 0.0850 AC: 410 AN: 4826

European-Finnish (FIN) AF: 0.0482 AC: 511 AN: 10598

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0561 AC: 3816 AN: 68014

Other (OTH) AF: 0.0649 AC: 137 AN: 2110

Alfa AF: 0.0586 Hom.: 57

Bravo AF: 0.0613

Asia WGS AF: 0.0770 AC: 268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		0.0060
PromoterAI		0.025	Neutral
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: rs3739390; hg19: chr8-6420490; COSMIC: COSV57336310;