rs56676181

Variant names:

• chr13-110449584-C-T
• rs56676181
• NM_001846.4:c.1079-95C>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.1079-95C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,203,346 control chromosomes in the GnomAD database, including 69,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7101 hom., cov: 33)
  • Exomes 𝑓: 0.34 (62411 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.243
• Publications: 3 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=-0.9).
• BP6: Variant 13-110449584-C-T is Benign according to our data. Variant chr13-110449584-C-T is described in ClinVar as Benign. ClinVar VariationId is 1258504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1079-95C>T		intron_variant	Intron 18 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1079-95C>T		intron_variant	Intron 18 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43354 AN: 152048 Hom.: 7096 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.340 AC: 357197 AN: 1051180 Hom.: 62411 AF XY: 0.342 AC XY: 177752 AN XY: 520458

African (AFR) AF: 0.118 AC: 2827 AN: 24040

American (AMR) AF: 0.185 AC: 3761 AN: 20356

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 4623 AN: 18236

East Asian (EAS) AF: 0.266 AC: 8858 AN: 33256

South Asian (SAS) AF: 0.331 AC: 19617 AN: 59284

European-Finnish (FIN) AF: 0.404 AC: 18020 AN: 44552

Middle Eastern (MID) AF: 0.197 AC: 896 AN: 4544

European-Non Finnish (NFE) AF: 0.355 AC: 284559 AN: 801486

Other (OTH) AF: 0.309 AC: 14036 AN: 45426

GnomAD4 genome AF: 0.285 AC: 43361 AN: 152166 Hom.: 7101 Cov.: 33 AF XY: 0.285 AC XY: 21235 AN XY: 74386

African (AFR) AF: 0.133 AC: 5509 AN: 41536

American (AMR) AF: 0.206 AC: 3145 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 949 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1392 AN: 5176

South Asian (SAS) AF: 0.324 AC: 1562 AN: 4818

European-Finnish (FIN) AF: 0.405 AC: 4282 AN: 10582

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25521 AN: 67968

Other (OTH) AF: 0.261 AC: 553 AN: 2116

Alfa AF: 0.330 Hom.: 13893

Bravo AF: 0.259

Asia WGS AF: 0.277 AC: 966 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: 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	-0.90
CADD	Benign	0.85
DANN	Benign	0.63
PhyloP100		-0.24
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: rs56676181; hg19: chr13-111101931; COSMIC: COSV64636529;