NM_001846.4:c.1012-23G>A

Variant names:

• chr13-110446775-G-A
• rs7326449
• NM_001846.4:c.1012-23G>A

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.1012-23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.787 in 1,602,554 control chromosomes in the GnomAD database, including 499,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.74 (42633 hom., cov: 31)
  • Exomes 𝑓: 0.79 (456908 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.64
• Publications: 12 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 13-110446775-G-A is Benign according to our data. Variant chr13-110446775-G-A is described in ClinVar as Benign. ClinVar VariationId is 1217364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.1012-23G>A		intron_variant	Intron 17 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.1012-23G>A		intron_variant	Intron 17 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113150 AN: 151942 Hom.: 42613 Cov.: 31

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.869

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.779

GnomAD2 exomes AF: 0.746 AC: 185483 AN: 248700 AF XY: 0.752

Gnomad AFR exome AF: 0.657

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.867

Gnomad EAS exome AF: 0.594

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.813

Gnomad OTH exome AF: 0.775

GnomAD4 exome AF: 0.791 AC: 1147819 AN: 1450494 Hom.: 456908 Cov.: 27 AF XY: 0.791 AC XY: 570153 AN XY: 720548

African (AFR) AF: 0.657 AC: 21894 AN: 33312

American (AMR) AF: 0.665 AC: 29625 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 22552 AN: 26008

East Asian (EAS) AF: 0.613 AC: 24149 AN: 39368

South Asian (SAS) AF: 0.721 AC: 61954 AN: 85878

European-Finnish (FIN) AF: 0.694 AC: 36679 AN: 52874

Middle Eastern (MID) AF: 0.850 AC: 4870 AN: 5732

European-Non Finnish (NFE) AF: 0.815 AC: 899043 AN: 1102924

Other (OTH) AF: 0.786 AC: 47053 AN: 59858

GnomAD4 genome AF: 0.745 AC: 113213 AN: 152060 Hom.: 42633 Cov.: 31 AF XY: 0.737 AC XY: 54787 AN XY: 74320

African (AFR) AF: 0.657 AC: 27231 AN: 41456

American (AMR) AF: 0.732 AC: 11195 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.869 AC: 3018 AN: 3472

East Asian (EAS) AF: 0.604 AC: 3101 AN: 5138

South Asian (SAS) AF: 0.718 AC: 3464 AN: 4824

European-Finnish (FIN) AF: 0.685 AC: 7245 AN: 10572

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.813 AC: 55249 AN: 67990

Other (OTH) AF: 0.777 AC: 1639 AN: 2110

Alfa AF: 0.798 Hom.: 28838

Bravo AF: 0.743

Asia WGS AF: 0.651 AC: 2267 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

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

Jul 22, 2021

Genome-Nilou Lab

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	-0.94
CADD	Benign	0.0010
DANN	Benign	0.68
PhyloP100		-2.6
BranchPoint Hunter		1.0
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: rs7326449; hg19: chr13-111099122; COSMIC: COSV64634083;