rs190336010

Variant names:

• chr2-151553828-A-G
• rs190336010
• NM_001164507.2:c.19626T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6 BP7 BS1 BS2_Supporting

The NM_001164508.2(NEB):​c.19626T>C​(p.Asp6542Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,607,176 control chromosomes in the GnomAD database, including 5 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: NEB NM_001164508.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002023
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.798
• 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, 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-151553828-A-G is Benign according to our data. Variant chr2-151553828-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167329.
• BP7: Synonymous conserved (PhyloP=-0.798 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00137 (208/152346) while in subpopulation AMR AF = 0.00307 (47/15304). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.19626T>C	p.Asp6542Asp	splice_region synonymous	Exon 126 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.19626T>C	p.Asp6542Asp	splice_region synonymous	Exon 126 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.19626T>C	p.Asp6542Asp	splice_region synonymous	Exon 126 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.19626T>C	p.Asp6542Asp	splice_region synonymous	Exon 126 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19626T>C	p.Asp6542Asp	splice_region synonymous	Exon 126 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.14523T>C	p.Asp4841Asp	splice_region synonymous	Exon 99 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00128 AC: 312 AN: 244442 AF XY: 0.00133

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00162 AC: 2357 AN: 1454830 Hom.: 5 Cov.: 31 AF XY: 0.00161 AC XY: 1164 AN XY: 722834

African (AFR) AF: 0.000360 AC: 12 AN: 33374

American (AMR) AF: 0.00137 AC: 61 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.000973 AC: 25 AN: 25706

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 85222

European-Finnish (FIN) AF: 0.000207 AC: 11 AN: 53076

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5690

European-Non Finnish (NFE) AF: 0.00194 AC: 2149 AN: 1107560

Other (OTH) AF: 0.00160 AC: 96 AN: 60104

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74490

African (AFR) AF: 0.000457 AC: 19 AN: 41576

American (AMR) AF: 0.00307 AC: 47 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 68044

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00187 Hom.: 3

Bravo AF: 0.00139

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Nemaline myopathy 2 (3)
-	1	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0010
DANN	Benign	0.31
PhyloP100		-0.80
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.060		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: rs190336010; hg19: chr2-152410342;