rs113095802

Variant names:

• chr2-151724252-A-G
• rs113095802
• NM_001164507.2:c.612+8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.612+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,605,928 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (60 hom., cov: 31)
  • Exomes 𝑓: 0.018 (312 hom.)
• Consequence: NEB NM_001164508.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002785
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.343
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151724252-A-G is Benign according to our data. Variant chr2-151724252-A-G is described in ClinVar as Benign. ClinVar VariationId is 129753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0235 (3584/152198) while in subpopulation AFR AF = 0.0397 (1650/41538). AF 95% confidence interval is 0.0381. There are 60 homozygotes in GnomAd4. There are 1712 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 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.612+8T>C		splice_region intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.612+8T>C		splice_region intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.612+8T>C		splice_region 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.612+8T>C		splice_region intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.612+8T>C		splice_region intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.612+8T>C		splice_region intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3570 AN: 152080 Hom.: 60 Cov.: 31

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.0239

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0269

GnomAD2 exomes AF: 0.0186 AC: 4556 AN: 244552 AF XY: 0.0194

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.00822

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.00417

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0183 AC: 26561 AN: 1453730 Hom.: 312 Cov.: 29 AF XY: 0.0187 AC XY: 13496 AN XY: 723124

African (AFR) AF: 0.0429 AC: 1429 AN: 33334

American (AMR) AF: 0.00880 AC: 390 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 1229 AN: 26012

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39622

South Asian (SAS) AF: 0.0301 AC: 2562 AN: 85228

European-Finnish (FIN) AF: 0.0123 AC: 654 AN: 53278

Middle Eastern (MID) AF: 0.0315 AC: 181 AN: 5748

European-Non Finnish (NFE) AF: 0.0168 AC: 18612 AN: 1106064

Other (OTH) AF: 0.0238 AC: 1431 AN: 60140

GnomAD4 genome AF: 0.0235 AC: 3584 AN: 152198 Hom.: 60 Cov.: 31 AF XY: 0.0230 AC XY: 1712 AN XY: 74410

African (AFR) AF: 0.0397 AC: 1650 AN: 41538

American (AMR) AF: 0.0150 AC: 230 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 149 AN: 3468

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5178

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4810

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1197 AN: 68004

Other (OTH) AF: 0.0266 AC: 56 AN: 2104

Alfa AF: 0.0215 Hom.: 23

Bravo AF: 0.0236

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Nemaline myopathy 2 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.066
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: rs113095802; hg19: chr2-152580766;