rs2229812

Variant names:

• chr2-227032170-C-T
• rs2229812
• NM_000092.5:c.3684G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000092.5(COL4A4):​c.3684G>A​(p.Lys1228Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,613,548 control chromosomes in the GnomAD database, including 161,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16881 hom., cov: 33)
  • Exomes 𝑓: 0.44 (144735 hom.)
• Consequence: COL4A4 NM_000092.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.447
• Publications: 24 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-227032170-C-T is Benign according to our data. Variant chr2-227032170-C-T is described in ClinVar as Benign. ClinVar VariationId is 255032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.3684G>A	p.Lys1228Lys	synonymous_variant	Exon 39 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.3684G>A	p.Lys1228Lys	synonymous_variant	Exon 39 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71072 AN: 152016 Hom.: 16850 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.413

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.436

GnomAD2 exomes AF: 0.474 AC: 118173 AN: 249372 AF XY: 0.472

Gnomad AFR exome AF: 0.536

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.514

Gnomad EAS exome AF: 0.400

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.442 AC: 645697 AN: 1461414 Hom.: 144735 Cov.: 55 AF XY: 0.444 AC XY: 322713 AN XY: 727026

African (AFR) AF: 0.529 AC: 17703 AN: 33474

American (AMR) AF: 0.528 AC: 23627 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13639 AN: 26132

East Asian (EAS) AF: 0.403 AC: 16017 AN: 39696

South Asian (SAS) AF: 0.569 AC: 49103 AN: 86244

European-Finnish (FIN) AF: 0.499 AC: 26641 AN: 53406

Middle Eastern (MID) AF: 0.398 AC: 2296 AN: 5768

European-Non Finnish (NFE) AF: 0.423 AC: 469797 AN: 1111596

Other (OTH) AF: 0.445 AC: 26874 AN: 60378

GnomAD4 genome AF: 0.468 AC: 71147 AN: 152134 Hom.: 16881 Cov.: 33 AF XY: 0.469 AC XY: 34895 AN XY: 74354

African (AFR) AF: 0.531 AC: 22021 AN: 41508

American (AMR) AF: 0.469 AC: 7168 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1734 AN: 3470

East Asian (EAS) AF: 0.388 AC: 2007 AN: 5172

South Asian (SAS) AF: 0.565 AC: 2724 AN: 4822

European-Finnish (FIN) AF: 0.493 AC: 5222 AN: 10592

Middle Eastern (MID) AF: 0.403 AC: 117 AN: 290

European-Non Finnish (NFE) AF: 0.425 AC: 28876 AN: 67970

Other (OTH) AF: 0.430 AC: 910 AN: 2116

Alfa AF: 0.452 Hom.: 8992

Bravo AF: 0.469

Asia WGS AF: 0.482 AC: 1679 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.410

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

- -

May 09, 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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 67% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 62. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Lys1228Lys in exon 39 of COL4A4: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 57.17% (9433/1650 0) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs2229812). -

not provided Benign:3

Apr 28, 2017

Athena Diagnostics

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 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. -

Autosomal recessive Alport syndrome Benign:1

Jul 10, 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	-0.69
CADD	Benign	0.37
DANN	Benign	0.45
PhyloP100		-0.45
Mutation Taster		=85/15	polymorphism

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: rs2229812; hg19: chr2-227896886; COSMIC: COSV61632591;