6-152122626-C-T

Variant names:

• chr6-152122626-C-T
• rs2295192
• NM_182961.4:c.26204G>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.26204G>A​(p.Arg8735Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,614,050 control chromosomes in the GnomAD database, including 1,349 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. R8735L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.043 (148 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1201 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0200
• Publications: 9 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=0.0023429394).
• BP6: Variant 6-152122626-C-T is Benign according to our data. Variant chr6-152122626-C-T is described in ClinVar as Benign. ClinVar VariationId is 130434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.063 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.26204G>A	p.Arg8735Gln	missense	Exon 146 of 146	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.2738G>A	p.Arg913Gln	missense	Exon 18 of 18	NP_001334631.1
	SYNE1	NM_033071.5		c.26060G>A	p.Arg8687Gln	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.26204G>A	p.Arg8735Gln	missense	Exon 146 of 146	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.2738G>A	p.Arg913Gln	missense	Exon 18 of 18	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.26060G>A	p.Arg8687Gln	missense	Exon 146 of 146	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6568 AN: 152122 Hom.: 149 Cov.: 33

Gnomad AFR AF: 0.0490

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0686

Gnomad FIN AF: 0.0629

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0516 AC: 12978 AN: 251304 AF XY: 0.0498

Gnomad AFR exome AF: 0.0515

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.0447

Gnomad EAS exome AF: 0.0574

Gnomad FIN exome AF: 0.0720

Gnomad NFE exome AF: 0.0351

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0353 AC: 51632 AN: 1461810 Hom.: 1201 Cov.: 33 AF XY: 0.0360 AC XY: 26146 AN XY: 727200

African (AFR) AF: 0.0473 AC: 1582 AN: 33478

American (AMR) AF: 0.0761 AC: 3401 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 1189 AN: 26136

East Asian (EAS) AF: 0.0549 AC: 2181 AN: 39700

South Asian (SAS) AF: 0.0620 AC: 5349 AN: 86256

European-Finnish (FIN) AF: 0.0719 AC: 3837 AN: 53398

Middle Eastern (MID) AF: 0.0536 AC: 309 AN: 5764

European-Non Finnish (NFE) AF: 0.0281 AC: 31276 AN: 1111970

Other (OTH) AF: 0.0415 AC: 2508 AN: 60388

GnomAD4 genome AF: 0.0432 AC: 6570 AN: 152240 Hom.: 148 Cov.: 33 AF XY: 0.0456 AC XY: 3393 AN XY: 74420

African (AFR) AF: 0.0490 AC: 2034 AN: 41536

American (AMR) AF: 0.0460 AC: 704 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3472

East Asian (EAS) AF: 0.0626 AC: 323 AN: 5162

South Asian (SAS) AF: 0.0691 AC: 333 AN: 4822

European-Finnish (FIN) AF: 0.0629 AC: 667 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0328 AC: 2229 AN: 68024

Other (OTH) AF: 0.0412 AC: 87 AN: 2114

Alfa AF: 0.0350 Hom.: 378

Bravo AF: 0.0419

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.0406 AC: 179

ESP6500EA AF: 0.0335 AC: 288

ExAC AF: 0.0509 AC: 6175

Asia WGS AF: 0.0720 AC: 251 AN: 3478

EpiCase AF: 0.0305

EpiControl AF: 0.0306

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	0.072
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.4
DANN	Benign	0.90
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.020
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.022
Sift	Benign	0.22	T
Sift4G	Benign	0.48	T
Polyphen		0.0040	B
Vest4		0.043
MPC		0.15
ClinPred		0.0024	T
GERP RS		1.3
Varity_R		0.060
gMVP		0.28
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: rs2295192; hg19: chr6-152443761; COSMIC: COSV55059389; COSMIC: COSV55059389;