NM_001164507.2:c.5802C>T

Variant names:

• chr2-151662303-G-A
• rs139963368
• NM_001164507.2:c.5802C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001164507.2(NEB):​c.5802C>T​(p.Gly1934Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,613,506 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (12 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.603
• Publications: 0 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-151662303-G-A is Benign according to our data. Variant chr2-151662303-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.603 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0053 (807/152194) while in subpopulation AFR AF = 0.0144 (600/41544). AF 95% confidence interval is 0.0135. There are 6 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. 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
	NEB	NM_001164507.2	MANE Plus Clinical	c.5802C>T	p.Gly1934Gly	synonymous	Exon 46 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.5802C>T	p.Gly1934Gly	synonymous	Exon 46 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.5802C>T	p.Gly1934Gly	synonymous	Exon 46 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.5802C>T	p.Gly1934Gly	synonymous	Exon 46 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.5802C>T	p.Gly1934Gly	synonymous	Exon 46 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.5802C>T	p.Gly1934Gly	synonymous	Exon 46 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152076 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00238 AC: 593 AN: 248804 AF XY: 0.00228

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00148 AC: 2166 AN: 1461312 Hom.: 12 Cov.: 31 AF XY: 0.00146 AC XY: 1058 AN XY: 726938

African (AFR) AF: 0.0129 AC: 433 AN: 33452

American (AMR) AF: 0.00436 AC: 195 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00235 AC: 203 AN: 86226

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53398

Middle Eastern (MID) AF: 0.00886 AC: 51 AN: 5758

European-Non Finnish (NFE) AF: 0.000983 AC: 1093 AN: 1111602

Other (OTH) AF: 0.00292 AC: 176 AN: 60350

GnomAD4 genome AF: 0.00530 AC: 807 AN: 152194 Hom.: 6 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74414

African (AFR) AF: 0.0144 AC: 600 AN: 41544

American (AMR) AF: 0.00491 AC: 75 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4814

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 67996

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00281 Hom.: 3

Bravo AF: 0.00583

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nemaline myopathy 2 (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	4.4
DANN	Benign	0.62
PhyloP100		-0.60
Mutation Taster		=99/1	polymorphism

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: rs139963368; hg19: chr2-152518817;