chr2-237345192-C-T

Variant names:

• chr2-237345192-C-T
• rs142002241
• NM_004369.4:c.7114G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_004369.4(COL6A3):​c.7114G>A​(p.Asp2372Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.42

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0784519).
• BP6: Variant 2-237345192-C-T is Benign according to our data. Variant chr2-237345192-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288387.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}. Variant chr2-237345192-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000257 (376/1461856) while in subpopulation NFE AF= 0.000314 (349/1111994). AF 95% confidence interval is 0.000286. There are 0 homozygotes in gnomad4_exome. There are 186 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7114G>A	p.Asp2372Asn	missense_variant	Exon 33 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6496G>A	p.Asp2166Asn	missense_variant	Exon 32 of 43		NP_476508.2
COL6A3	NM_057166.5	c.5293G>A	p.Asp1765Asn	missense_variant	Exon 30 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7114G>A	p.Asp2372Asn	missense_variant	Exon 33 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.5293G>A	p.Asp1765Asn	missense_variant	Exon 30 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.6496G>A	p.Asp2166Asn	missense_variant	Exon 32 of 43	5		ENSP00000315873.4
COL6A3	ENST00000491769.1	n.1368G>A		non_coding_transcript_exon_variant	Exon 10 of 20	5

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251238 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135820

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000257 AC: 376 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 186 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000292 Hom.: 1

Bravo AF: 0.000208

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Feb 07, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bethlem myopathy 1A Benign:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Benign	0.95
DEOGEN2	Benign	0.22	.;T;.;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.60	T;T;T;T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.8	.;L;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;N;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.33	T;T;T;.;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		1.0	D;D;.;.;D
Vest4		0.46
MVP		0.89
MPC		0.14
ClinPred		0.045	T
GERP RS		5.0
Varity_R		0.072
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs142002241; hg19: chr2-238253835;