rs78224483

Variant names:

• chr21-46001956-C-T
• rs78224483
• NM_001848.3:c.1957-5C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_StrongBP6_Strong

The NM_001848.3(COL6A1):c.1957-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0196 (AC=31,613) in the gnomAD database across 1,611,704 control chromosomes, including 389 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0254. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 34)
  • Exomes 𝑓: 0.020 (349 hom.)
• Consequence: COL6A1 NM_001848.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001802
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.836
• Publications: 2 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (12/12 total B/LB).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0254 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 389.; Very high cumulative gnomAD AC = 31613 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001848.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	COL6A1 NM_001848.3	MANE Select	c.1957-5C>T	splice_regionintron	Intron 30 of 34	Prot: NP_001839.2 UniProt:

COL6A1 NM_001848.3

MANE Select

HGVSc / HGVSpc.1957-5C>T

Exon rankIntron 30 of 34

splice_regionintron

Prot: NP_001839.2UniProt: A0A384P5H7P12109

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	COL6A1 ENST00000361866.8	TSL:1MANE Select	c.1957-5C>T	splice_regionintron	Intron 30 of 34	Prot: ENSP00000355180.3 UniProt:
	COL6A1 ENST00000498614.5	TSL:1	n.191-5C>T	splice_regionintron	Intron 1 of 5	Prot:
	COL6A1 ENST00000612273.2	TSL:5	c.82-5C>T	splice_regionintron	Intron 1 of 6	Prot: ENSP00000483630.2 UniProt:

COL6A1 ENST00000361866.8

TSL:1MANE Select

HGVSc / HGVSpc.1957-5C>T

Exon rankIntron 30 of 34

splice_regionintron

Prot: ENSP00000355180.3UniProt: P12109

COL6A1 ENST00000498614.5

TSL:1

HGVSc / HGVSpn.191-5C>T

Exon rankIntron 1 of 5

splice_regionintron

Prot:

COL6A1 ENST00000612273.2

TSL:5

HGVSc / HGVSpc.82-5C>T

Exon rankIntron 1 of 6

splice_regionintron

Prot: ENSP00000483630.2UniProt: A0A087X0S5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0172	AC:2615	Hom:40	AN:152142	Cov:34
GnomAD2 exomes	AF: 0.0171	AC:4123	Hom:	AN:241412	Cov:
GnomAD4 exome	AF: 0.0199	AC:28998	Hom:349	AN:1459444	Cov:35
GnomAD4 genome	AF: 0.0172	AC:2615	Hom:40	AN:152260	Cov:34
TOPMed (Bravo)	AF: 0.0143	AC:3787	Hom:53	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0234	AC:5803	Hom:91	AN:248490	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0107	AC:25	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0133	AC:4	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0153	AC:199	Hom:	AN:13002	Cov:
GenomeAsia100K	AF: 0.00231	AC:8	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00570	AC:1	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000330	AC:4	Hom:0	AN:122553	Cov:
Turkish Variome	AF: 0.0158	AC:96	Hom:3	AN:6060	Cov:
UK10K	AF: 0.0193	AC:146	Hom:	AN:7562	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0220	624	28418	0.0236	680	28844
SCHEMA(Schizophrenia)	0.0156	1518	97346	0.0203	3057	150920

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0073
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.046
DANN	Benign	0.55
GPN-Star LLR	N/A	-1.8
GPN-Star score	N/A	1.8
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.84

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0080
Pangolin (max)	Benign	0.090
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs78224483;

hg19: chr21-47421870;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar