rs2228558

Variant names:

• chr2-227147485-G-A
• rs2228558
• NM_000092.5:c.-2C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,612,518 control chromosomes in the GnomAD database, including 4,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (2209 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (2075 hom.)
• Consequence: COL4A4 NM_000092.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.433

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-227147485-G-A is Benign according to our data. Variant chr2-227147485-G-A is described in ClinVar as [Benign]. Clinvar id is 255011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227147485-G-A is described in Lovd as [Benign]. Variant chr2-227147485-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.-2C>T		5_prime_UTR_variant	Exon 2 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.-2C>T		5_prime_UTR_variant	Exon 2 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 14375 AN: 152028 Hom.: 2203 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0607

GnomAD3 exomes AF: 0.0244 AC: 6081 AN: 249360 Hom.: 891 AF XY: 0.0192 AC XY: 2599 AN XY: 135296

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00985 AC: 14382 AN: 1460372 Hom.: 2075 Cov.: 30 AF XY: 0.00868 AC XY: 6307 AN XY: 726592

Gnomad4 AFR exome AF: 0.339

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00436

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000558

Gnomad4 OTH exome AF: 0.0213

GnomAD4 genome AF: 0.0947 AC: 14409 AN: 152146 Hom.: 2209 Cov.: 32 AF XY: 0.0913 AC XY: 6794 AN XY: 74390

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0492 Hom.: 655

Bravo AF: 0.108

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.-2C>T in intron 2 of COL4A4: This variant is not expected to have clinical sig nificance because it has been identified in 33.3% (7981/23968) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs2228558). ACMG/AMP Criteria applied: BA1. -

Nov 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 23, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228558; hg19: chr2-228012201;