rs140688592

Variant names:

• chr2-151570566-C-A
• rs140688592
• NM_001164507.2:c.17049G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151570566-C-A
• chr2-151570566-C-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.17049G>T​(p.Ala5683Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00962 in 1,605,778 control chromosomes in the GnomAD database, including 101 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. A5683A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (95 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0360
• Publications: 2 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=-0.33).
• BP6: Variant 2-151570566-C-A is Benign according to our data. Variant chr2-151570566-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.036 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00683 (1039/152176) while in subpopulation NFE AF = 0.0106 (724/68018). AF 95% confidence interval is 0.01. There are 6 homozygotes in GnomAd4. There are 492 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_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.17049G>T	p.Ala5683Ala	synonymous	Exon 108 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.17049G>T	p.Ala5683Ala	synonymous	Exon 108 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.17049G>T	p.Ala5683Ala	synonymous	Exon 108 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.17049G>T	p.Ala5683Ala	synonymous	Exon 108 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.17049G>T	p.Ala5683Ala	synonymous	Exon 108 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11946G>T	p.Ala3982Ala	synonymous	Exon 81 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 1039 AN: 152062 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00937

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00499

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00649 AC: 1520 AN: 234334 AF XY: 0.00678

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.0000589

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00991 AC: 14406 AN: 1453602 Hom.: 95 Cov.: 33 AF XY: 0.00981 AC XY: 7080 AN XY: 722080

African (AFR) AF: 0.00114 AC: 38 AN: 33244

American (AMR) AF: 0.00533 AC: 234 AN: 43892

Ashkenazi Jewish (ASJ) AF: 0.00622 AC: 161 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.00511 AC: 431 AN: 84284

European-Finnish (FIN) AF: 0.00219 AC: 116 AN: 52946

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.0117 AC: 12923 AN: 1108222

Other (OTH) AF: 0.00827 AC: 497 AN: 60118

GnomAD4 genome AF: 0.00683 AC: 1039 AN: 152176 Hom.: 6 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74408

African (AFR) AF: 0.00217 AC: 90 AN: 41514

American (AMR) AF: 0.00936 AC: 143 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4808

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0106 AC: 724 AN: 68018

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00640 Hom.: 2

Bravo AF: 0.00692

Asia WGS AF: 0.00260 AC: 9 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)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	3.2
DANN	Benign	0.49
PhyloP100		0.036
PromoterAI		0.023	Neutral
Mutation Taster		=100/0	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: rs140688592; hg19: chr2-152427080;