chr2-227051208-T-C

Variant names:

• chr2-227051208-T-C
• rs2272205
• NM_000092.5:c.2969-50A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.2969-50A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 1,593,442 control chromosomes in the GnomAD database, including 7,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (539 hom., cov: 32)
  • Exomes 𝑓: 0.094 (6669 hom.)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.894
• Publications: 14 publications found

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• autosomal dominant Alport syndrome

  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 2-227051208-T-C is Benign according to our data. Variant chr2-227051208-T-C is described in ClinVar as Benign. ClinVar VariationId is 682773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000092.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	NM_000092.5	MANE Select	c.2969-50A>G		intron	N/A	NP_000083.3	P53420

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.2969-50A>G		intron	N/A	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12127 AN: 152062 Hom.: 537 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0732

Gnomad ASJ AF: 0.0851

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0621

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0880

GnomAD2 exomes AF: 0.0906 AC: 22490 AN: 248274 AF XY: 0.0944

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.0515

Gnomad ASJ exome AF: 0.0878

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.0636

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.0950

GnomAD4 exome AF: 0.0936 AC: 134950 AN: 1441262 Hom.: 6669 Cov.: 27 AF XY: 0.0950 AC XY: 68267 AN XY: 718308

African (AFR) AF: 0.0469 AC: 1550 AN: 33052

American (AMR) AF: 0.0530 AC: 2369 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0841 AC: 2184 AN: 25958

East Asian (EAS) AF: 0.175 AC: 6947 AN: 39604

South Asian (SAS) AF: 0.125 AC: 10726 AN: 85796

European-Finnish (FIN) AF: 0.0651 AC: 3474 AN: 53330

Middle Eastern (MID) AF: 0.129 AC: 737 AN: 5734

European-Non Finnish (NFE) AF: 0.0926 AC: 101268 AN: 1093378

Other (OTH) AF: 0.0954 AC: 5695 AN: 59716

GnomAD4 genome AF: 0.0798 AC: 12140 AN: 152180 Hom.: 539 Cov.: 32 AF XY: 0.0796 AC XY: 5922 AN XY: 74388

African (AFR) AF: 0.0482 AC: 2001 AN: 41518

American (AMR) AF: 0.0730 AC: 1116 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0851 AC: 295 AN: 3468

East Asian (EAS) AF: 0.182 AC: 940 AN: 5154

South Asian (SAS) AF: 0.134 AC: 644 AN: 4816

European-Finnish (FIN) AF: 0.0621 AC: 659 AN: 10604

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0917 AC: 6234 AN: 68012

Other (OTH) AF: 0.0932 AC: 197 AN: 2114

Alfa AF: 0.0885 Hom.: 2573

Bravo AF: 0.0773

Asia WGS AF: 0.154 AC: 533 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.73
DANN	Benign	0.50
PhyloP100		-0.89
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: rs2272205; hg19: chr2-227915924; COSMIC: COSV61631547;