rs146310692

Variant names:

• chr2-151662137-C-T
• rs146310692
• NM_001164507.2:c.5968G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001164508.2(NEB):​c.5968G>A​(p.Glu1990Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,609,152 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: NEB NM_001164508.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001490
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.904
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042778254).
• BP6: Variant 2-151662137-C-T is Benign according to our data. Variant chr2-151662137-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331500.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 = 0.00287 (437/152250) while in subpopulation AFR AF = 0.0098 (407/41544). AF 95% confidence interval is 0.00901. There are 1 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.5968G>A	p.Glu1990Lys	missense splice_region	Exon 46 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.5968G>A	p.Glu1990Lys	missense splice_region	Exon 46 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.5968G>A	p.Glu1990Lys	missense splice_region	Exon 46 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.5968G>A	p.Glu1990Lys	missense splice_region	Exon 46 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.5968G>A	p.Glu1990Lys	missense splice_region	Exon 46 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.5968G>A	p.Glu1990Lys	missense splice_region	Exon 46 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00983

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000680 AC: 168 AN: 247198 AF XY: 0.000582

Gnomad AFR exome AF: 0.00947

Gnomad AMR exome AF: 0.000467

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000321 AC: 468 AN: 1456902 Hom.: 3 Cov.: 30 AF XY: 0.000270 AC XY: 196 AN XY: 724704

African (AFR) AF: 0.0106 AC: 353 AN: 33330

American (AMR) AF: 0.000516 AC: 23 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5752

European-Non Finnish (NFE) AF: 0.0000325 AC: 36 AN: 1108336

Other (OTH) AF: 0.000765 AC: 46 AN: 60164

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74438

African (AFR) AF: 0.00980 AC: 407 AN: 41544

American (AMR) AF: 0.00157 AC: 24 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00134 Hom.: 1

Bravo AF: 0.00337

ESP6500AA AF: 0.00823 AC: 31

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000836 AC: 101

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nemaline myopathy 2 (3)
-	-	3	not provided (3)
-	-	1	NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N
PhyloP100		0.90
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.064
Sift	Benign	0.61	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.27
MVP		0.28
MPC		0.058
ClinPred		0.0047	T
GERP RS		3.8
Varity_R		0.065
gMVP		0.32
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0
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: rs146310692; hg19: chr2-152518651; COSMIC: COSV51161144;