rs11894996

Variant names:

• chr2-151552782-G-A
• rs11894996
• NM_001164507.2:c.19732-6C>T

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.19732-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,603,208 control chromosomes in the GnomAD database, including 430 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: 32)
  • Exomes 𝑓: 0.021 (370 hom.)
• Consequence: NEB NM_001164508.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004533
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.920
• 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, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.81).
• BP6: Variant 2-151552782-G-A is Benign according to our data. Variant chr2-151552782-G-A is described in ClinVar as Benign. ClinVar VariationId is 129719.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 = 0.0244 (3707/152190) while in subpopulation AFR AF = 0.0386 (1602/41528). AF 95% confidence interval is 0.037. There are 60 homozygotes in GnomAd4. There are 1839 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.19732-6C>T		splice_region intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.19732-6C>T		splice_region intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.19732-6C>T		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.19732-6C>T		splice_region intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19732-6C>T		splice_region intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.14629-6C>T		splice_region intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3696 AN: 152072 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0193 AC: 4643 AN: 240150 AF XY: 0.0185

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00901

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.0000579

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0210 AC: 30446 AN: 1451018 Hom.: 370 Cov.: 28 AF XY: 0.0203 AC XY: 14648 AN XY: 721736

African (AFR) AF: 0.0400 AC: 1333 AN: 33310

American (AMR) AF: 0.00987 AC: 434 AN: 43978

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 594 AN: 25962

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39452

South Asian (SAS) AF: 0.00710 AC: 604 AN: 85070

European-Finnish (FIN) AF: 0.0352 AC: 1870 AN: 53132

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5746

European-Non Finnish (NFE) AF: 0.0220 AC: 24345 AN: 1104388

Other (OTH) AF: 0.0200 AC: 1200 AN: 59980

GnomAD4 genome AF: 0.0244 AC: 3707 AN: 152190 Hom.: 60 Cov.: 32 AF XY: 0.0247 AC XY: 1839 AN XY: 74392

African (AFR) AF: 0.0386 AC: 1602 AN: 41528

American (AMR) AF: 0.0110 AC: 168 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4816

European-Finnish (FIN) AF: 0.0405 AC: 428 AN: 10576

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0195 AC: 1328 AN: 68008

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0232 Hom.: 20

Bravo AF: 0.0233

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Nemaline myopathy 2 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.42
DANN	Benign	0.55
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0020
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: rs11894996; hg19: chr2-152409296; COSMIC: COSV50807348;