8-14090612-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_139167.4(SGCZ):c.770A>G(p.Lys257Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCZ NM_139167.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.96

Genes affected

SGCZ (HGNC:14075): (sarcoglycan zeta) The zeta-sarcoglycan gene measures over 465 kb and localizes to 8p22. This protein is part of the sarcoglycan complex, a group of 6 proteins. The sarcoglycans are all N-glycosylated transmembrane proteins with a short intra-cellular domain, a single transmembrane region and a large extra-cellular domain containing a carboxyl-terminal cluster with several conserved cysteine residues. The sarcoglycan complex is part of the dystrophin-associated glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extra-cellular matrix. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085035086).
• BP6: Variant 8-14090612-T-C is Benign according to our data. Variant chr8-14090612-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2474554.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCZ	NM_139167.4	c.770A>G	p.Lys257Arg	missense_variant	8/8	ENST00000382080.6
SGCZ	NM_001322879.2	c.668A>G	p.Lys223Arg	missense_variant	7/7
SGCZ	NM_001322880.2	c.647A>G	p.Lys216Arg	missense_variant	7/7
SGCZ	NM_001322881.2	c.425A>G	p.Lys142Arg	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCZ	ENST00000382080.6	c.770A>G	p.Lys257Arg	missense_variant	8/8	5	NM_139167.4	P1
SGCZ	ENST00000421524.6	c.629A>G	p.Lys210Arg	missense_variant	6/6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249648 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	18
Dann	Benign	0.18
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.41	N;N
REVEL	Benign	0.16
Sift	Benign	0.39	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	B;B
Vest4		0.093
MutPred		0.29		.;Loss of ubiquitination at K210 (P = 0.0141);
MVP		0.12
MPC		0.0095
ClinPred		0.060	T
GERP RS		4.5
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758122469; hg19: chr8-13948121;