rs75118047

Variant names:

• chr2-151694638-A-C
• rs75118047
• NM_001164507.2:c.1675-9T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151694638-A-C
• chr2-151694638-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.1675-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,567,594 control chromosomes in the GnomAD database, including 90 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 0.0038 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (80 hom.)
• Consequence: NEB NM_001164508.2 intron
• Scores: Splicing: ADA: 0.006701
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0850
• 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

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-151694638-A-C is Benign according to our data. Variant chr2-151694638-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

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.1675-9T>G		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.1675-9T>G		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.1675-9T>G		intron	N/A	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.1675-9T>G		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.1675-9T>G		intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000489048.1	TSL:1	n.574-9T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152180 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00793

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0579

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00791 AC: 1410 AN: 178324 AF XY: 0.00743

Gnomad AFR exome AF: 0.000395

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0644

Gnomad FIN exome AF: 0.00715

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00519

GnomAD4 exome AF: 0.00255 AC: 3610 AN: 1415296 Hom.: 80 Cov.: 31 AF XY: 0.00254 AC XY: 1778 AN XY: 699704

African (AFR) AF: 0.000155 AC: 5 AN: 32348

American (AMR) AF: 0.0122 AC: 455 AN: 37186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.0550 AC: 2059 AN: 37434

South Asian (SAS) AF: 0.00186 AC: 151 AN: 81012

European-Finnish (FIN) AF: 0.00799 AC: 405 AN: 50682

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 0.000241 AC: 262 AN: 1086872

Other (OTH) AF: 0.00463 AC: 272 AN: 58730

GnomAD4 genome AF: 0.00381 AC: 581 AN: 152298 Hom.: 10 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74466

African (AFR) AF: 0.000505 AC: 21 AN: 41572

American (AMR) AF: 0.00792 AC: 121 AN: 15286

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

East Asian (EAS) AF: 0.0575 AC: 298 AN: 5184

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4820

European-Finnish (FIN) AF: 0.00800 AC: 85 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000950 Hom.: 2

Bravo AF: 0.00413

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		-0.085
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0067
dbscSNV1_RF	Benign	0.31
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: rs75118047; hg19: chr2-152551152; COSMIC: COSV51420428;