NM_000337.6:c.294+8T>C

Variant names:

• chr5-156508710-T-C
• rs11748588
• NM_000337.6:c.294+8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000337.6(SGCD):​c.294+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,505,194 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene SGCD is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0061 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (41 hom.)
• Consequence: SGCD NM_000337.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008836
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.104
• Publications: 1 publications found

Genes affected

SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

SGCD Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2F

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy 1L

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Specifications for SGCD are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-156508710-T-C is Benign according to our data. Variant chr5-156508710-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00612 (932/152314) while in subpopulation NFE AF = 0.00788 (536/68022). AF 95% confidence interval is 0.00733. There are 3 homozygotes in GnomAd4. There are 504 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000337.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	NM_000337.6	MANE Select	c.294+8T>C		splice_region intron	N/A	NP_000328.2
	SGCD	NM_001128209.2		c.291+8T>C		splice_region intron	N/A	NP_001121681.1	Q92629-1
	SGCD	NM_172244.3		c.294+8T>C		splice_region intron	N/A	NP_758447.1	Q92629-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	ENST00000337851.9	TSL:1 MANE Select	c.294+8T>C		splice_region intron	N/A	ENSP00000338343.4	Q92629-2
	SGCD	ENST00000435422.7	TSL:1	c.291+8T>C		splice_region intron	N/A	ENSP00000403003.2	Q92629-1
	SGCD	ENST00000959784.1		c.345+8T>C		splice_region intron	N/A	ENSP00000629843.1

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 932 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00663 AC: 1540 AN: 232398 AF XY: 0.00674

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00758

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00668 AC: 9042 AN: 1352880 Hom.: 41 Cov.: 20 AF XY: 0.00658 AC XY: 4455 AN XY: 677194

African (AFR) AF: 0.000878 AC: 27 AN: 30744

American (AMR) AF: 0.00340 AC: 137 AN: 40300

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 275 AN: 24648

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39038

South Asian (SAS) AF: 0.00223 AC: 179 AN: 80376

European-Finnish (FIN) AF: 0.0176 AC: 934 AN: 52972

Middle Eastern (MID) AF: 0.00402 AC: 22 AN: 5470

European-Non Finnish (NFE) AF: 0.00701 AC: 7170 AN: 1022772

Other (OTH) AF: 0.00525 AC: 297 AN: 56560

GnomAD4 genome AF: 0.00612 AC: 932 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74484

African (AFR) AF: 0.00137 AC: 57 AN: 41576

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00788 AC: 536 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00698 Hom.: 3

Bravo AF: 0.00504

Asia WGS AF: 0.00260 AC: 10 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2F (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Dilated cardiomyopathy 1L (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Qualitative or quantitative defects of delta-sarcoglycan (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.0
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: rs11748588; hg19: chr5-155935720;