12-26230745-C-T

Position:

• chr12-26230745-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005086.5(SSPN):​c.401C>T​(p.Thr134Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,054 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (15 hom.)
• Consequence: SSPN NM_005086.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.631

Genes affected

SSPN (HGNC:11322): (sarcospan) This gene encodes a member of the dystrophin-glycoprotein complex (DGC). The DGC spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Two alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Oct 2008]

ENSG00000255750 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021695793).
• BP6: Variant 12-26230745-C-T is Benign according to our data. Variant chr12-26230745-C-T is described in ClinVar as [Benign]. Clinvar id is 711572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-26230745-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00803 (1223/152354) while in subpopulation AFR AF= 0.0277 (1151/41580). AF 95% confidence interval is 0.0264. There are 18 homozygotes in gnomad4. There are 573 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SSPN	NM_005086.5	c.401C>T	p.Thr134Met	missense_variant	3/3	ENST00000242729.7	NP_005077.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SSPN	ENST00000242729.7	c.401C>T	p.Thr134Met	missense_variant	3/3	1	NM_005086.5	ENSP00000242729.2

Frequencies

GnomAD3 genomes AF: 0.00799 AC: 1216 AN: 152236 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00207 AC: 518 AN: 250724 Hom.: 8 AF XY: 0.00143 AC XY: 194 AN XY: 135492

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000839 AC: 1227 AN: 1461700 Hom.: 15 Cov.: 31 AF XY: 0.000701 AC XY: 510 AN XY: 727120

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00803 AC: 1223 AN: 152354 Hom.: 18 Cov.: 33 AF XY: 0.00769 AC XY: 573 AN XY: 74510

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00152 Hom.: 6

Bravo AF: 0.00937

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00253 AC: 307

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.8
DANN	Benign	0.81
DEOGEN2	Benign	0.0039	T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.70	T;.;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	.;.;.;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.95	N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0070	.;.;.;B
Vest4		0.13, 0.12, 0.091
MVP		0.14
MPC		0.51
ClinPred		0.011	T
GERP RS		-7.0
Varity_R		0.016
gMVP		0.40

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: rs34055748; hg19: chr12-26383678;