rs2274544

Variant names:

• chr13-110493286-C-T
• rs2274544
• NM_001846.4:c.3634+4C>T

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.3634+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,613,924 control chromosomes in the GnomAD database, including 5,526 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (539 hom., cov: 32)
  • Exomes 𝑓: 0.068 (4987 hom.)
• Consequence: COL4A2 NM_001846.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005183
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0630
• Publications: 11 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 13-110493286-C-T is Benign according to our data. Variant chr13-110493286-C-T is described in ClinVar as Benign. ClinVar VariationId is 311164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.3634+4C>T		splice_region_variant, intron_variant	Intron 39 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.3634+4C>T		splice_region_variant, intron_variant	Intron 39 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11590 AN: 152176 Hom.: 540 Cov.: 32

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0740

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0642

GnomAD2 exomes AF: 0.0910 AC: 22693 AN: 249258 AF XY: 0.0959

Gnomad AFR exome AF: 0.0657

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.159

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.0553

Gnomad OTH exome AF: 0.0858

GnomAD4 exome AF: 0.0677 AC: 99024 AN: 1461630 Hom.: 4987 Cov.: 33 AF XY: 0.0717 AC XY: 52110 AN XY: 727132

African (AFR) AF: 0.0698 AC: 2338 AN: 33476

American (AMR) AF: 0.0559 AC: 2501 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2783 AN: 26126

East Asian (EAS) AF: 0.187 AC: 7406 AN: 39698

South Asian (SAS) AF: 0.189 AC: 16259 AN: 86252

European-Finnish (FIN) AF: 0.153 AC: 8162 AN: 53330

Middle Eastern (MID) AF: 0.0905 AC: 522 AN: 5766

European-Non Finnish (NFE) AF: 0.0489 AC: 54331 AN: 1111880

Other (OTH) AF: 0.0782 AC: 4722 AN: 60386

GnomAD4 genome AF: 0.0762 AC: 11610 AN: 152294 Hom.: 539 Cov.: 32 AF XY: 0.0829 AC XY: 6176 AN XY: 74466

African (AFR) AF: 0.0656 AC: 2729 AN: 41570

American (AMR) AF: 0.0737 AC: 1129 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3472

East Asian (EAS) AF: 0.172 AC: 887 AN: 5170

South Asian (SAS) AF: 0.198 AC: 957 AN: 4828

European-Finnish (FIN) AF: 0.158 AC: 1680 AN: 10608

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0537 AC: 3654 AN: 68022

Other (OTH) AF: 0.0650 AC: 137 AN: 2108

Alfa AF: 0.0606 Hom.: 162

Bravo AF: 0.0639

Asia WGS AF: 0.162 AC: 561 AN: 3474

EpiCase AF: 0.0553

EpiControl AF: 0.0536

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Jun 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Porencephaly 2 Benign:1

Jan 12, 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	-0.70
CADD	Benign	13
DANN	Benign	0.64
PhyloP100		0.063
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.040		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: rs2274544; hg19: chr13-111145633; COSMIC: COSV64632511;