13-110466103-C-T

Variant names:

• chr13-110466103-C-T
• rs41275112
• NM_001846.4:c.2038+41C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001846.4(COL4A2):​c.2038+41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,594,818 control chromosomes in the GnomAD database, including 413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (31 hom., cov: 33)
  • Exomes 𝑓: 0.021 (382 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• Publications: 2 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 13-110466103-C-T is Benign according to our data. Variant chr13-110466103-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1214410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0159 (2418/152324) while in subpopulation NFE AF = 0.0233 (1584/68038). AF 95% confidence interval is 0.0223. There are 31 homozygotes in GnomAd4. There are 1121 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2418 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.2038+41C>T		intron	N/A	NP_001837.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.2038+41C>T		intron	N/A	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.2119+41C>T		intron	N/A	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.2038+41C>T		intron	N/A	ENSP00000383027.4

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2417 AN: 152206 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0148 AC: 3601 AN: 243130 AF XY: 0.0148

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0209 AC: 30184 AN: 1442494 Hom.: 382 Cov.: 30 AF XY: 0.0205 AC XY: 14629 AN XY: 714518

African (AFR) AF: 0.00723 AC: 238 AN: 32904

American (AMR) AF: 0.0104 AC: 444 AN: 42760

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 653 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 39276

South Asian (SAS) AF: 0.00462 AC: 391 AN: 84634

European-Finnish (FIN) AF: 0.0104 AC: 555 AN: 53164

Middle Eastern (MID) AF: 0.0151 AC: 86 AN: 5688

European-Non Finnish (NFE) AF: 0.0243 AC: 26668 AN: 1098864

Other (OTH) AF: 0.0193 AC: 1149 AN: 59548

GnomAD4 genome AF: 0.0159 AC: 2418 AN: 152324 Hom.: 31 Cov.: 33 AF XY: 0.0151 AC XY: 1121 AN XY: 74474

African (AFR) AF: 0.00832 AC: 346 AN: 41576

American (AMR) AF: 0.0156 AC: 238 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4822

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1584 AN: 68038

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.0198 Hom.: 12

Bravo AF: 0.0161

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.45
PhyloP100		1.8
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: rs41275112; hg19: chr13-111118450;