rs2295191

Positions:

• chr6-152122621-C-A
• chr6-152122621-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_182961.4(SYNE1):​c.26209G>T​(p.Gly8737Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11249453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.26209G>T	p.Gly8737Cys	missense_variant	146/146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.2743G>T	p.Gly915Cys	missense_variant	18/18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.26209G>T	p.Gly8737Cys	missense_variant	146/146	1	NM_182961.4	ENSP00000356224	P1
SYNE1	ENST00000354674.5	c.2743G>T	p.Gly915Cys	missense_variant	18/18	5	NM_001347702.2	ENSP00000346701

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251344 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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 AF: 0.00000205 AC: 3 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.18
DANN	Benign	0.69
DEOGEN2	Benign	0.21	T;.;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.1	N;.;D;N;D
REVEL	Benign	0.012
Sift	Benign	0.22	T;.;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.063
MutPred		0.38		Loss of helix (P = 0.0626);.;.;.;.;
MVP		0.17
MPC		0.14
ClinPred		0.022	T
GERP RS		-4.8
Varity_R		0.13
gMVP		0.38

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2295191; hg19: chr6-152443756;