2-151575797-T-C

Variant names:

• chr2-151575797-T-C
• rs33988153
• NM_001164507.2:c.16911A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.16911A>G​(p.Pro5637Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,576,262 control chromosomes in the GnomAD database, including 41,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P5637P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3156 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38727 hom.)
• Consequence: NEB NM_001164508.2 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.245
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-151575797-T-C is Benign according to our data. Variant chr2-151575797-T-C is described in ClinVar as Benign. ClinVar VariationId is 95106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.245 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 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.16911A>G	p.Pro5637Pro	splice_region synonymous	Exon 107 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.16911A>G	p.Pro5637Pro	splice_region synonymous	Exon 107 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.16911A>G	p.Pro5637Pro	splice_region synonymous	Exon 107 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.16911A>G	p.Pro5637Pro	splice_region synonymous	Exon 107 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16911A>G	p.Pro5637Pro	splice_region synonymous	Exon 107 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11808A>G	p.Pro3936Pro	splice_region synonymous	Exon 80 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26647 AN: 152122 Hom.: 3153 Cov.: 32

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.196 AC: 48787 AN: 248414 AF XY: 0.206

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.000947

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.224 AC: 319001 AN: 1424022 Hom.: 38727 Cov.: 26 AF XY: 0.226 AC XY: 160918 AN XY: 710574

African (AFR) AF: 0.0353 AC: 1167 AN: 33038

American (AMR) AF: 0.108 AC: 4795 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7497 AN: 25930

East Asian (EAS) AF: 0.000758 AC: 30 AN: 39574

South Asian (SAS) AF: 0.214 AC: 18225 AN: 85310

European-Finnish (FIN) AF: 0.251 AC: 13365 AN: 53312

Middle Eastern (MID) AF: 0.251 AC: 1423 AN: 5660

European-Non Finnish (NFE) AF: 0.241 AC: 260045 AN: 1077494

Other (OTH) AF: 0.211 AC: 12454 AN: 59118

GnomAD4 genome AF: 0.175 AC: 26646 AN: 152240 Hom.: 3156 Cov.: 32 AF XY: 0.174 AC XY: 12966 AN XY: 74444

African (AFR) AF: 0.0445 AC: 1852 AN: 41582

American (AMR) AF: 0.150 AC: 2285 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3468

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5188

South Asian (SAS) AF: 0.202 AC: 973 AN: 4818

European-Finnish (FIN) AF: 0.249 AC: 2643 AN: 10600

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 17024 AN: 67986

Other (OTH) AF: 0.185 AC: 391 AN: 2112

Alfa AF: 0.221 Hom.: 3628

Bravo AF: 0.158

Asia WGS AF: 0.0840 AC: 292 AN: 3478

EpiCase AF: 0.263

EpiControl AF: 0.262

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Nemaline myopathy 2 (4)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.6
DANN	Benign	0.61
PhyloP100		0.24
Mutation Taster		=95/5	polymorphism (auto)

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: rs33988153; hg19: chr2-152432311; COSMIC: COSV51417516;