rs146460133

Variant names:

• chr2-151692278-G-A
• rs146460133
• NM_001164507.2:c.1981C>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_001164508.2(NEB):​c.1981C>T​(p.Leu661Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000664 in 1,613,710 control chromosomes in the GnomAD database, including 8 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. L661L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.92
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-151692278-G-A is Benign according to our data. Variant chr2-151692278-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00357 (544/152288) while in subpopulation AFR AF = 0.0125 (520/41558). AF 95% confidence interval is 0.0116. There are 4 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1981C>T	p.Leu661Leu	synonymous	Exon 21 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.1981C>T	p.Leu661Leu	synonymous	Exon 21 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.1981C>T	p.Leu661Leu	synonymous	Exon 21 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.1981C>T	p.Leu661Leu	synonymous	Exon 21 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.1981C>T	p.Leu661Leu	synonymous	Exon 21 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000489048.1	TSL:1	n.880C>T		non_coding_transcript_exon	Exon 9 of 12

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 541 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.000831 AC: 207 AN: 248988 AF XY: 0.000629

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000361 AC: 528 AN: 1461422 Hom.: 4 Cov.: 31 AF XY: 0.000320 AC XY: 233 AN XY: 727024

African (AFR) AF: 0.0133 AC: 444 AN: 33462

American (AMR) AF: 0.000649 AC: 29 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111694

Other (OTH) AF: 0.000746 AC: 45 AN: 60360

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152288 Hom.: 4 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74468

African (AFR) AF: 0.0125 AC: 520 AN: 41558

American (AMR) AF: 0.00111 AC: 17 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00394

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.0
DANN	Benign	0.72
PhyloP100		1.9
Mutation Taster		=97/3	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: rs146460133; hg19: chr2-152548792;