chr14-64139936-G-C

Variant names:

• chr14-64139936-G-C
• rs17825431
• NM_182914.3:c.14844-5G>C

Variant summary

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

The NM_182914.3(SYNE2):​c.14844-5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,276 control chromosomes in the GnomAD database, including 9,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (831 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8877 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001197
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.475
• Publications: 11 publications found

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ovarian dysgenesis 8

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-64139936-G-C is Benign according to our data. Variant chr14-64139936-G-C is described in ClinVar as Benign. ClinVar VariationId is 130478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. 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
	SYNE2	NM_182914.3	MANE Select	c.14844-5G>C		splice_region intron	N/A	NP_878918.2
	SYNE2	NM_015180.6		c.14844-5G>C		splice_region intron	N/A	NP_055995.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.14844-5G>C		splice_region intron	N/A	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.14844-5G>C		splice_region intron	N/A	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.4377-5G>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0903 AC: 13736 AN: 152080 Hom.: 831 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.0622

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0839

GnomAD2 exomes AF: 0.110 AC: 27531 AN: 251256 AF XY: 0.107

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.104 AC: 152624 AN: 1461078 Hom.: 8877 Cov.: 33 AF XY: 0.104 AC XY: 75385 AN XY: 726878

African (AFR) AF: 0.0252 AC: 845 AN: 33476

American (AMR) AF: 0.120 AC: 5350 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 1696 AN: 26118

East Asian (EAS) AF: 0.221 AC: 8748 AN: 39666

South Asian (SAS) AF: 0.0688 AC: 5936 AN: 86246

European-Finnish (FIN) AF: 0.160 AC: 8517 AN: 53336

Middle Eastern (MID) AF: 0.0295 AC: 170 AN: 5766

European-Non Finnish (NFE) AF: 0.104 AC: 115360 AN: 1111380

Other (OTH) AF: 0.0994 AC: 6002 AN: 60370

GnomAD4 genome AF: 0.0902 AC: 13733 AN: 152198 Hom.: 831 Cov.: 32 AF XY: 0.0935 AC XY: 6957 AN XY: 74390

African (AFR) AF: 0.0276 AC: 1148 AN: 41554

American (AMR) AF: 0.0983 AC: 1503 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 225 AN: 3468

East Asian (EAS) AF: 0.243 AC: 1257 AN: 5170

South Asian (SAS) AF: 0.0625 AC: 301 AN: 4816

European-Finnish (FIN) AF: 0.173 AC: 1830 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7206 AN: 68004

Other (OTH) AF: 0.0825 AC: 174 AN: 2108

Alfa AF: 0.0795 Hom.: 208

Bravo AF: 0.0836

Asia WGS AF: 0.128 AC: 444 AN: 3478

EpiCase AF: 0.0893

EpiControl AF: 0.0926

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.028
DANN	Benign	0.61
PhyloP100		-0.47
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17825431; hg19: chr14-64606654; COSMIC: COSV59952641; COSMIC: COSV59952641;