NM_001846.4:c.*76T>C

Variant names:

• chr13-110512267-T-C
• rs422733
• NM_001846.4:c.*76T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):​c.*76T>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 0.56 in 1,477,380 control chromosomes in the GnomAD database, including 234,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (22951 hom., cov: 31)
  • Exomes 𝑓: 0.56 (211488 hom.)
• Consequence: COL4A2 NM_001846.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900
• Publications: 14 publications found

Genes affected

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

COL4A2 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289010 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-110512267-T-C is Benign according to our data. Variant chr13-110512267-T-C is described in ClinVar as Benign. ClinVar VariationId is 311200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.*76T>C		3_prime_UTR_variant	Exon 48 of 48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.*76T>C		3_prime_UTR_variant	Exon 48 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.548 AC: 82884 AN: 151262 Hom.: 22930 Cov.: 31

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.570

GnomAD4 exome AF: 0.561 AC: 744244 AN: 1326000 Hom.: 211488 Cov.: 32 AF XY: 0.559 AC XY: 362572 AN XY: 649038

African (AFR) AF: 0.562 AC: 16018 AN: 28492

American (AMR) AF: 0.560 AC: 12064 AN: 21544

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 12740 AN: 21872

East Asian (EAS) AF: 0.249 AC: 8713 AN: 34994

South Asian (SAS) AF: 0.470 AC: 33404 AN: 71102

European-Finnish (FIN) AF: 0.497 AC: 18310 AN: 36878

Middle Eastern (MID) AF: 0.593 AC: 2757 AN: 4652

European-Non Finnish (NFE) AF: 0.580 AC: 609746 AN: 1051682

Other (OTH) AF: 0.557 AC: 30492 AN: 54784

GnomAD4 genome AF: 0.548 AC: 82951 AN: 151380 Hom.: 22951 Cov.: 31 AF XY: 0.541 AC XY: 39998 AN XY: 73954

African (AFR) AF: 0.562 AC: 23167 AN: 41252

American (AMR) AF: 0.574 AC: 8755 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1989 AN: 3460

East Asian (EAS) AF: 0.247 AC: 1275 AN: 5154

South Asian (SAS) AF: 0.450 AC: 2156 AN: 4796

European-Finnish (FIN) AF: 0.474 AC: 4937 AN: 10410

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38836 AN: 67758

Other (OTH) AF: 0.564 AC: 1179 AN: 2092

Alfa AF: 0.572 Hom.: 11033

Bravo AF: 0.556

Asia WGS AF: 0.418 AC: 1454 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 16, 2019

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

- -

Porencephaly 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.1
DANN	Benign	0.65
PhyloP100		-0.0090
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: rs422733; hg19: chr13-111164614;