rs35686968

Variant names:

• chr2-151724301-C-G
• rs35686968
• NM_001164507.2:c.571G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164508.2(NEB):​c.571G>C​(p.Glu191Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,613,012 control chromosomes in the GnomAD database, including 553 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (44 hom., cov: 31)
  • Exomes 𝑓: 0.024 (509 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 7.49
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010740876).
• BP6: Variant 2-151724301-C-G is Benign according to our data. Variant chr2-151724301-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129748.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2429/152182) while in subpopulation NFE AF = 0.0259 (1759/68010). AF 95% confidence interval is 0.0249. There are 44 homozygotes in GnomAd4. There are 1148 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 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.571G>C	p.Glu191Gln	missense	Exon 8 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.571G>C	p.Glu191Gln	missense	Exon 8 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.571G>C	p.Glu191Gln	missense	Exon 8 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.571G>C	p.Glu191Gln	missense	Exon 8 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.571G>C	p.Glu191Gln	missense	Exon 8 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.571G>C	p.Glu191Gln	missense	Exon 8 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2429 AN: 152064 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00976

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.0163 AC: 4051 AN: 248062 AF XY: 0.0172

Gnomad AFR exome AF: 0.00408

Gnomad AMR exome AF: 0.00531

Gnomad ASJ exome AF: 0.00409

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0239 AC: 34883 AN: 1460830 Hom.: 509 Cov.: 30 AF XY: 0.0236 AC XY: 17122 AN XY: 726580

African (AFR) AF: 0.00341 AC: 114 AN: 33466

American (AMR) AF: 0.00587 AC: 262 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00394 AC: 103 AN: 26114

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39684

South Asian (SAS) AF: 0.0105 AC: 902 AN: 86036

European-Finnish (FIN) AF: 0.0213 AC: 1139 AN: 53360

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5762

European-Non Finnish (NFE) AF: 0.0280 AC: 31106 AN: 1111462

Other (OTH) AF: 0.0204 AC: 1229 AN: 60338

GnomAD4 genome AF: 0.0160 AC: 2429 AN: 152182 Hom.: 44 Cov.: 31 AF XY: 0.0154 AC XY: 1148 AN XY: 74368

African (AFR) AF: 0.00486 AC: 202 AN: 41524

American (AMR) AF: 0.0111 AC: 170 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00977 AC: 47 AN: 4810

European-Finnish (FIN) AF: 0.0210 AC: 222 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1759 AN: 68010

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.0233 Hom.: 39

Bravo AF: 0.0142

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00503 AC: 20

ESP6500EA AF: 0.0255 AC: 212

ExAC AF: 0.0163 AC: 1974

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0225

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	1	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.32
Sift	Benign	0.19	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MPC		0.34
ClinPred		0.013	T
GERP RS		6.0
Varity_R		0.34
gMVP		0.56
Mutation Taster		=99/1	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: rs35686968; hg19: chr2-152580815;