chr6-152122254-C-T

Variant names:

• chr6-152122254-C-T
• rs12681
• NM_182961.4:c.*182G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.*182G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 873,974 control chromosomes in the GnomAD database, including 19,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4258 hom., cov: 33)
  • Exomes 𝑓: 0.20 (14987 hom.)
• Consequence: SYNE1 NM_182961.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.129

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-152122254-C-T is Benign according to our data. Variant chr6-152122254-C-T is described in ClinVar as [Benign]. Clinvar id is 355803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152122254-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.*182G>A		3_prime_UTR_variant	Exon 146 of 146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.*182G>A		3_prime_UTR_variant	Exon 18 of 18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255	c.*182G>A		3_prime_UTR_variant	Exon 146 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674	c.*182G>A		3_prime_UTR_variant	Exon 18 of 18	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35269 AN: 152044 Hom.: 4258 Cov.: 33

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.199 AC: 143496 AN: 721814 Hom.: 14987 Cov.: 10 AF XY: 0.194 AC XY: 72182 AN XY: 371612

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.232 AC: 35288 AN: 152160 Hom.: 4258 Cov.: 33 AF XY: 0.230 AC XY: 17125 AN XY: 74402

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.214

Alfa AF: 0.200 Hom.: 3147

Bravo AF: 0.231

Asia WGS AF: 0.150 AC: 523 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.2
DANN	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12681; hg19: chr6-152443389;