2-219482799-G-T

Position:

• chr2-219482799-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005876.5(SPEG):​c.5581G>T​(p.Ala1861Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPEG NM_005876.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

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]

ASIC4-AS1 (HGNC:40960): (ASIC4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEG	NM_005876.5	c.5581G>T	p.Ala1861Ser	missense_variant	29/41	ENST00000312358.12	NP_005867.3
ASIC4-AS1	XR_923921.2	n.392-390C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEG	ENST00000312358.12	c.5581G>T	p.Ala1861Ser	missense_variant	29/41	5	NM_005876.5	ENSP00000311684	P1
ASIC4-AS1	ENST00000429882.1	n.183-390C>A		intron_variant, non_coding_transcript_variant		3
SPEG	ENST00000485813.5	n.4824G>T		non_coding_transcript_exon_variant	27/39	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461508 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The c.5581G>T (p.A1861S) alteration is located in exon 29 (coding exon 29) of the SPEG gene. This alteration results from a G to T substitution at nucleotide position 5581, causing the alanine (A) at amino acid position 1861 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	0.079
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.11
Sift	Benign	0.39	T
Sift4G	Benign	0.075	T
Polyphen		0.93	P
Vest4		0.42
MutPred		0.28		Gain of disorder (P = 0.0411);
MVP		0.63
MPC		1.5
ClinPred		0.86	D
GERP RS		3.8
Varity_R		0.063
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220347521;