rs2747653

Variant names:

• chr6-152124922-T-C
• rs2747653
• NM_182961.4:c.26154-2246A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182961.4(SYNE1):​c.26154-2246A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,146 control chromosomes in the GnomAD database, including 3,105 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3105 hom., cov: 33)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 4 publications found

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]

ESR1 Gene-Disease associations (from GenCC):

• estrogen resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.26154-2246A>G		intron	N/A	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.2688-2246A>G		intron	N/A	NP_001334631.1
	SYNE1	NM_033071.5		c.26010-2246A>G		intron	N/A	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.26154-2246A>G		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.2688-2246A>G		intron	N/A	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.26010-2246A>G		intron	N/A	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30664 AN: 152030 Hom.: 3108 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.197

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.202 AC: 30663 AN: 152146 Hom.: 3105 Cov.: 33 AF XY: 0.201 AC XY: 14948 AN XY: 74374

African (AFR) AF: 0.192 AC: 7963 AN: 41504

American (AMR) AF: 0.189 AC: 2889 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3464

East Asian (EAS) AF: 0.126 AC: 651 AN: 5176

South Asian (SAS) AF: 0.109 AC: 528 AN: 4824

European-Finnish (FIN) AF: 0.290 AC: 3070 AN: 10590

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14325 AN: 67982

Other (OTH) AF: 0.194 AC: 407 AN: 2102

Alfa AF: 0.202 Hom.: 702

Bravo AF: 0.197

Asia WGS AF: 0.142 AC: 494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.4
DANN	Benign	0.60
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2747653; hg19: chr6-152446057;