rs376780156

Positions:

chr5-156344676-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_000337.6: c.191T>C variant in SGCD is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 64 (p.Ile64Thr). The highest minor allele frequency of this variant is 0.0001293 in the Admixed American population of gnomAD v2.1.1 (4/30926 exome chromosomes), which is greater than the LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.63 (PP3, BP4 not met). In summary, there is currently insufficient evidence to determine whether this variant is pathogenic or benign and it is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP(LGMD VCEP specifications version 1.0.0; 01/08/2025): no codes applied. LINK:https://erepo.genome.network/evrepo/ui/classification/CA308788/MONDO:0015152/186

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

SGCD
NM_000337.6 missense, splice_region

Scores

Splicing: ADA: 0.1962

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 6.16

Variant links:

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 links:

LOC124901120 (HGNC:):

LOC124901120 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCD	NM_000337.6 linkuse as main transcript	c.191T>C	p.Ile64Thr	missense_variant, splice_region_variant	3/9	ENST00000337851.9	NP_000328.2	Q92629-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SGCD	ENST00000337851.9 linkuse as main transcript	c.191T>C	p.Ile64Thr	missense_variant, splice_region_variant	3/9	1	NM_000337.6	ENSP00000338343.4	Q92629-2
SGCD	ENST00000435422.7 linkuse as main transcript	c.188T>C	p.Ile63Thr	missense_variant, splice_region_variant	2/8	1		ENSP00000403003.2	Q92629-1
SGCD	ENST00000517913.5 linkuse as main transcript	c.191T>C	p.Ile64Thr	missense_variant, splice_region_variant	5/10	5		ENSP00000429378.1	Q92629-3
SGCD	ENST00000524347.2 linkuse as main transcript	n.191T>C		splice_region_variant, non_coding_transcript_exon_variant	3/6	5		ENSP00000430794.1	E5RI34

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000767

AC:

AN:

234638

Hom.:

AF XY:

0.0000626

AC XY:

AN XY:

127726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000129

Gnomad ASJ exome

AF:

0.000410

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000556

Gnomad OTH exome

AF:

0.000716

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1446290

Hom.:

Cov.:

AF XY:

0.0000529

AC XY:

AN XY:

718992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000141

Gnomad4 ASJ exome

AF:

0.000579

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000462

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 18, 2022	- -

Autosomal recessive limb-girdle muscular dystrophy type 2F

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 64 of the SGCD protein (p.Ile64Thr). This variant is present in population databases (rs376780156, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SGCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 202088). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2023

The p.I64T variant (also known as c.191T>C), located in coding exon 2 of the SGCD gene, results from a T to C substitution at nucleotide position 191. The isoleucine at codon 64 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Dilated cardiomyopathy 1L

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

.;T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.72

T;T;T

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

0.29

.;N;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.14

N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.49

T;T;T

Polyphen

0.99

D;P;P

Vest4

0.88

MVP

0.95

MPC

0.55

ClinPred

0.15

GERP RS

5.3

Varity_R

0.17

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.20

dbscSNV1_RF

Benign

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over