rs2295191

Variant names:

• chr6-152122621-C-T
• rs2295191
• NM_182961.4:c.26209G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.26209G>A​(p.Gly8737Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,614,110 control chromosomes in the GnomAD database, including 518 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G8737V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (69 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (449 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.54
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00387156).
• BP6: Variant 6-152122621-C-T is Benign according to our data. Variant chr6-152122621-C-T is described in ClinVar as Benign. ClinVar VariationId is 130435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0923 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.26209G>A	p.Gly8737Ser	missense	Exon 146 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.2743G>A	p.Gly915Ser	missense	Exon 18 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.26065G>A	p.Gly8689Ser	missense	Exon 146 of 146	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.26209G>A	p.Gly8737Ser	missense	Exon 146 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.2743G>A	p.Gly915Ser	missense	Exon 18 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.26065G>A	p.Gly8689Ser	missense	Exon 146 of 146	ENSP00000396024.1	A0A0C4DG40

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1651 AN: 152160 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.0721

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.0185 AC: 4661 AN: 251344 AF XY: 0.0191

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.0607

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00816 AC: 11932 AN: 1461832 Hom.: 449 Cov.: 32 AF XY: 0.00895 AC XY: 6510 AN XY: 727210

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.000581 AC: 26 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26136

East Asian (EAS) AF: 0.109 AC: 4342 AN: 39700

South Asian (SAS) AF: 0.0355 AC: 3066 AN: 86258

European-Finnish (FIN) AF: 0.0578 AC: 3086 AN: 53406

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000541 AC: 602 AN: 1111980

Other (OTH) AF: 0.0120 AC: 724 AN: 60388

GnomAD4 genome AF: 0.0109 AC: 1653 AN: 152278 Hom.: 69 Cov.: 33 AF XY: 0.0149 AC XY: 1112 AN XY: 74444

African (AFR) AF: 0.000577 AC: 24 AN: 41570

American (AMR) AF: 0.00150 AC: 23 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.0994 AC: 513 AN: 5160

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4828

European-Finnish (FIN) AF: 0.0721 AC: 765 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68022

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00508 Hom.: 46

Bravo AF: 0.00507

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0176 AC: 2139

Asia WGS AF: 0.0650 AC: 225 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.26
DANN	Benign	0.75
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.019
Sift	Benign	0.97	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.064
MPC		0.13
ClinPred		0.0023	T
GERP RS		-4.8
Varity_R		0.058
gMVP		0.32
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2295191; hg19: chr6-152443756; COSMIC: COSV54934875; COSMIC: COSV54934875;