2-237365858-G-T

Variant names:

• chr2-237365858-G-T
• rs143389941
• NM_004369.4:c.5678C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6_Moderate BS1

The NM_004369.4(COL6A3):​c.5678C>A​(p.Thr1893Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,880 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.45

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 -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.136859).
• BP6: Variant 2-237365858-G-T is Benign according to our data. Variant chr2-237365858-G-T is described in ClinVar as [Benign]. Clinvar id is 1004714.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000164 (24/1461880) while in subpopulation AMR AF= 0.000492 (22/44724). AF 95% confidence interval is 0.000333. There are 1 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.5678C>A	p.Thr1893Lys	missense_variant	Exon 12 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5060C>A	p.Thr1687Lys	missense_variant	Exon 11 of 43		NP_476508.2
COL6A3	NM_057166.5	c.3857C>A	p.Thr1286Lys	missense_variant	Exon 9 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.5678C>A	p.Thr1893Lys	missense_variant	Exon 12 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.3857C>A	p.Thr1286Lys	missense_variant	Exon 9 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5060C>A	p.Thr1687Lys	missense_variant	Exon 11 of 43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251424 Hom.: 1 AF XY: 0.0000441 AC XY: 6 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461880 Hom.: 1 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Benign:1

Jul 21, 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	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.21	.;T;.;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T;T;T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N;N;N;.;N
REVEL	Benign	0.088
Sift	Uncertain	0.016	D;D;D;.;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.56	P;B;.;.;P
Vest4		0.35
MutPred		0.46		.;Gain of methylation at T1893 (P = 0.0071);.;.;.;
MVP		0.56
MPC		0.41
ClinPred		0.15	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.54

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: rs143389941; hg19: chr2-238274501;