13-110436109-A-T

Variant names:

• chr13-110436109-A-T
• rs41275108
• NM_001846.4:c.727-160A>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.727-160A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 1,071,630 control chromosomes in the GnomAD database, including 1,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (167 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1515 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 5 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

ENSG00000310266 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-110436109-A-T is Benign according to our data. Variant chr13-110436109-A-T is described in ClinVar as Benign. ClinVar VariationId is 1278604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.727-160A>T		intron_variant	Intron 12 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.727-160A>T		intron_variant	Intron 12 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 5989 AN: 150790 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.00876

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0716

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0515 AC: 11401 AN: 221416 AF XY: 0.0530

Gnomad AFR exome AF: 0.00861

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.0653

Gnomad NFE exome AF: 0.0457

Gnomad OTH exome AF: 0.0472

GnomAD4 exome AF: 0.0497 AC: 45746 AN: 920726 Hom.: 1515 Cov.: 12 AF XY: 0.0505 AC XY: 24070 AN XY: 476754

African (AFR) AF: 0.00750 AC: 170 AN: 22670

American (AMR) AF: 0.0251 AC: 1023 AN: 40794

Ashkenazi Jewish (ASJ) AF: 0.0252 AC: 560 AN: 22226

East Asian (EAS) AF: 0.155 AC: 5717 AN: 36846

South Asian (SAS) AF: 0.0717 AC: 5120 AN: 71384

European-Finnish (FIN) AF: 0.0601 AC: 2496 AN: 41512

Middle Eastern (MID) AF: 0.0301 AC: 121 AN: 4014

European-Non Finnish (NFE) AF: 0.0447 AC: 28581 AN: 638824

Other (OTH) AF: 0.0461 AC: 1958 AN: 42456

GnomAD4 genome AF: 0.0397 AC: 5988 AN: 150904 Hom.: 167 Cov.: 32 AF XY: 0.0411 AC XY: 3028 AN XY: 73758

African (AFR) AF: 0.00873 AC: 353 AN: 40430

American (AMR) AF: 0.0300 AC: 457 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.140 AC: 723 AN: 5168

South Asian (SAS) AF: 0.0717 AC: 342 AN: 4772

European-Finnish (FIN) AF: 0.0699 AC: 737 AN: 10542

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0467 AC: 3172 AN: 67972

Other (OTH) AF: 0.0427 AC: 90 AN: 2108

Alfa AF: 0.0380 Hom.: 22

Bravo AF: 0.0353

Asia WGS AF: 0.0970 AC: 338 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

- -

Jul 09, 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	-0.91
CADD	Benign	0.13
DANN	Benign	0.57
PhyloP100		-1.3
PromoterAI		0.012	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: rs41275108; hg19: chr13-111088456; COSMIC: COSV64626244;