2-219434991-G-A

Variant names:

• chr2-219434991-G-A
• rs576016632
• NM_005876.5:c.14G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_005876.5(SPEG):​c.14G>A​(p.Arg5Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000153 in 1,505,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: SPEG NM_005876.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.22

Genes affected

SPEG (HGNC:16901): (striated muscle enriched protein kinase) This gene encodes a protein with similarity to members of the myosin light chain kinase family. This protein family is required for myocyte cytoskeletal development. Along with the desmin gene, expression of this gene may be controlled by the desmin locus control region. Mutations in this gene are associated with centronuclear myopathy 5. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18733826).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000854 (13/152214) while in subpopulation AMR AF= 0.000457 (7/15308). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEG	NM_005876.5	c.14G>A	p.Arg5Gln	missense_variant	Exon 1 of 41	ENST00000312358.12	NP_005867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEG	ENST00000312358.12	c.14G>A	p.Arg5Gln	missense_variant	Exon 1 of 41	5	NM_005876.5	ENSP00000311684.7

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152098 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00000739 AC: 10 AN: 1353648 Hom.: 0 Cov.: 32 AF XY: 0.00000599 AC XY: 4 AN XY: 668268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000602

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000469

Gnomad4 OTH exome AF: 0.0000531

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74428

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.000147

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14G>A (p.R5Q) alteration is located in exon 1 (coding exon 1) of the SPEG gene. This alteration results from a G to A substitution at nucleotide position 14, causing the arginine (R) at amino acid position 5 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

May 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 5 of the SPEG protein (p.Arg5Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPEG-related conditions. 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: "Deleterious"; PolyPhen-2: "Benign"; 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.46		Loss of methylation at R5 (P = 0.0152);
MVP		0.65
MPC		0.84
ClinPred		0.69	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.27

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: rs576016632; hg19: chr2-220299713;