chr2-151561253-C-A

Variant names:

• chr2-151561253-C-A
• rs115631125
• NM_001164507.2:c.19056G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001164508.2(NEB):​c.19056G>T​(p.Thr6352Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,608,264 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T6352T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (63 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -5.15
• 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-151561253-C-A is Benign according to our data. Variant chr2-151561253-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00395 (601/152260) while in subpopulation SAS AF = 0.0145 (70/4820). AF 95% confidence interval is 0.0118. There are 3 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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.19056G>T	p.Thr6352Thr	synonymous	Exon 122 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.19056G>T	p.Thr6352Thr	synonymous	Exon 122 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.19056G>T	p.Thr6352Thr	synonymous	Exon 122 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.19056G>T	p.Thr6352Thr	synonymous	Exon 122 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19056G>T	p.Thr6352Thr	synonymous	Exon 122 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.13953G>T	p.Thr4651Thr	synonymous	Exon 95 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00575 AC: 1381 AN: 240254 AF XY: 0.00656

Gnomad AFR exome AF: 0.000876

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00583

Gnomad OTH exome AF: 0.00679

GnomAD4 exome AF: 0.00612 AC: 8913 AN: 1456004 Hom.: 63 Cov.: 31 AF XY: 0.00650 AC XY: 4705 AN XY: 723712

African (AFR) AF: 0.00117 AC: 39 AN: 33390

American (AMR) AF: 0.00291 AC: 128 AN: 43968

Ashkenazi Jewish (ASJ) AF: 0.00912 AC: 237 AN: 25982

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39500

South Asian (SAS) AF: 0.0166 AC: 1418 AN: 85214

European-Finnish (FIN) AF: 0.00330 AC: 175 AN: 53026

Middle Eastern (MID) AF: 0.00816 AC: 47 AN: 5758

European-Non Finnish (NFE) AF: 0.00586 AC: 6496 AN: 1108992

Other (OTH) AF: 0.00617 AC: 371 AN: 60174

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00412 AC XY: 307 AN XY: 74442

African (AFR) AF: 0.00123 AC: 51 AN: 41542

American (AMR) AF: 0.00281 AC: 43 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4820

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68026

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00605 Hom.: 1

Bravo AF: 0.00389

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Nemaline myopathy 2 (3)
-	-	2	not provided (2)
-	-	1	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.047
DANN	Benign	0.32
PhyloP100		-5.1
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs115631125; hg19: chr2-152417767;