rs2295190

Variant names:

• chr6-152122609-G-T
• rs2295190
• NM_182961.4:c.26221C>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.26221C>A​(p.Leu8741Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,614,114 control chromosomes in the GnomAD database, including 15,499 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1082 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14417 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.64
• Publications: 42 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018197596).
• BP6: Variant 6-152122609-G-T is Benign according to our data. Variant chr6-152122609-G-T is described in ClinVar as Benign. ClinVar VariationId is 130436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 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.26221C>A	p.Leu8741Met	missense	Exon 146 of 146	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.2755C>A	p.Leu919Met	missense	Exon 18 of 18	NP_001334631.1
	SYNE1	NM_033071.5		c.26077C>A	p.Leu8693Met	missense	Exon 146 of 146	NP_149062.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.26221C>A	p.Leu8741Met	missense	Exon 146 of 146	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.2755C>A	p.Leu919Met	missense	Exon 18 of 18	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.26077C>A	p.Leu8693Met	missense	Exon 146 of 146	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15685 AN: 152156 Hom.: 1081 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0549

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0616

Gnomad SAS AF: 0.0932

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.115 AC: 28800 AN: 251356 AF XY: 0.118

Gnomad AFR exome AF: 0.0276

Gnomad AMR exome AF: 0.0432

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.0552

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.136 AC: 198384 AN: 1461840 Hom.: 14417 Cov.: 33 AF XY: 0.135 AC XY: 97926 AN XY: 727218

African (AFR) AF: 0.0262 AC: 876 AN: 33478

American (AMR) AF: 0.0435 AC: 1946 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2907 AN: 26136

East Asian (EAS) AF: 0.0825 AC: 3276 AN: 39700

South Asian (SAS) AF: 0.0923 AC: 7965 AN: 86258

European-Finnish (FIN) AF: 0.196 AC: 10486 AN: 53404

Middle Eastern (MID) AF: 0.0596 AC: 344 AN: 5768

European-Non Finnish (NFE) AF: 0.147 AC: 163495 AN: 1111984

Other (OTH) AF: 0.117 AC: 7089 AN: 60392

GnomAD4 genome AF: 0.103 AC: 15692 AN: 152274 Hom.: 1082 Cov.: 32 AF XY: 0.102 AC XY: 7604 AN XY: 74430

African (AFR) AF: 0.0318 AC: 1323 AN: 41582

American (AMR) AF: 0.0548 AC: 838 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 387 AN: 3472

East Asian (EAS) AF: 0.0617 AC: 319 AN: 5166

South Asian (SAS) AF: 0.0931 AC: 449 AN: 4824

European-Finnish (FIN) AF: 0.195 AC: 2064 AN: 10600

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10010 AN: 68008

Other (OTH) AF: 0.0799 AC: 169 AN: 2114

Alfa AF: 0.130 Hom.: 5158

Bravo AF: 0.0875

TwinsUK AF: 0.144 AC: 533

ALSPAC AF: 0.156 AC: 600

ESP6500AA AF: 0.0345 AC: 152

ESP6500EA AF: 0.140 AC: 1202

ExAC AF: 0.118 AC: 14339

Asia WGS AF: 0.0960 AC: 337 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.129

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.17
Sift	Benign	0.030	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.25
MPC		0.51
ClinPred		0.012	T
GERP RS		0.63
Varity_R		0.30
gMVP		0.32
Mutation Taster		=95/5	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2295190; hg19: chr6-152443744; COSMIC: COSV54985860; COSMIC: COSV54985860;