chr6-152308637-G-A

Variant names:

• chr6-152308637-G-A
• rs886044642
• NM_182961.4:c.17203-5C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_182961.4(SYNE1):​c.17203-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000556 in 1,327,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00056 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYNE1 NM_182961.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006666
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.194
• Publications: 1 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]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-152308637-G-A is Benign according to our data. Variant chr6-152308637-G-A is described in ClinVar as Benign. ClinVar VariationId is 706436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.17203-5C>T		splice_region_variant, intron_variant	Intron 90 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.17203-5C>T		splice_region_variant, intron_variant	Intron 90 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.16994-9C>T		intron_variant	Intron 89 of 145	1		ENSP00000396024.1
SYNE1	ENST00000367256.9	n.895-5C>T		splice_region_variant, intron_variant	Intron 5 of 60	1
SYNE1	ENST00000409694.6	n.787-5C>T		splice_region_variant, intron_variant	Intron 3 of 58	1

Frequencies

GnomAD3 genomes AF: 0.000563 AC: 76 AN: 135078 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000306

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000257

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00124 AC: 217 AN: 175394 AF XY: 0.00111

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.000274

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00225

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00336

GnomAD4 exome AF: 0.000556 AC: 738 AN: 1327034 Hom.: 0 Cov.: 37 AF XY: 0.000596 AC XY: 394 AN XY: 661006

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00245 AC: 71 AN: 28970

American (AMR) AF: 0.00132 AC: 43 AN: 32468

Ashkenazi Jewish (ASJ) AF: 0.000514 AC: 12 AN: 23324

East Asian (EAS) AF: 0.000196 AC: 7 AN: 35782

South Asian (SAS) AF: 0.000870 AC: 66 AN: 75838

European-Finnish (FIN) AF: 0.00180 AC: 78 AN: 43256

Middle Eastern (MID) AF: 0.00102 AC: 5 AN: 4900

European-Non Finnish (NFE) AF: 0.000400 AC: 411 AN: 1027534

Other (OTH) AF: 0.000819 AC: 45 AN: 54962

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000563 AC: 76 AN: 135104 Hom.: 0 Cov.: 25 AF XY: 0.000719 AC XY: 47 AN XY: 65332

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000748 AC: 27 AN: 36084

American (AMR) AF: 0.00 AC: 0 AN: 13902

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 1 AN: 3268

East Asian (EAS) AF: 0.00 AC: 0 AN: 4856

South Asian (SAS) AF: 0.00 AC: 0 AN: 4286

European-Finnish (FIN) AF: 0.00423 AC: 32 AN: 7566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000257 AC: 16 AN: 62142

Other (OTH) AF: 0.00 AC: 0 AN: 1912

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00349 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Jul 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.5
DANN	Benign	0.47
PhyloP100		0.19
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067

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

Other links and lift over

dbSNP: rs886044642; hg19: chr6-152629772;