chr14-63853026-C-T

Variant names:

• chr14-63853026-C-T
• rs886050575
• NM_182914.3:c.-169C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_182914.3(SYNE2):​c.-169C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 151,590 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYNE2 NM_182914.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.218
• Publications: 0 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]

SYNE2 Gene-Disease associations (from GenCC):

• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

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

ENSG00000306681 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00127 (193/151590) while in subpopulation AMR AF = 0.00322 (49/15208). AF 95% confidence interval is 0.0025. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 193 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.-169C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_182914.3	MANE Select	c.-169C>T		5_prime_UTR	Exon 1 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.-169C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 115	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.-169C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.-169C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000341472.9	TSL:1	c.-169C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000344528.5	Q8WXH0-8

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 151590 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00322

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00130

Gnomad OTH AF: 0.000481

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 50 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 26

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00127 AC: 193 AN: 151590 Hom.: 1 Cov.: 32 AF XY: 0.00157 AC XY: 116 AN XY: 74008

African (AFR) AF: 0.000218 AC: 9 AN: 41372

American (AMR) AF: 0.00322 AC: 49 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00442 AC: 46 AN: 10408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00130 AC: 88 AN: 67840

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.000842

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.8
DANN	Benign	0.90
PhyloP100		-0.22
PromoterAI		-0.17	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs886050575; hg19: chr14-64319744;