NM_001164507.2:c.17644C>G

Variant names:

• chr2-151568408-G-C
• rs769673154
• NM_001164507.2:c.17644C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3 BP6_Moderate

The NM_001164507.2(NEB):​c.17644C>G​(p.Arg5882Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5882Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.51
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• BP6: Variant 2-151568408-G-C is Benign according to our data. Variant chr2-151568408-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2171970.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. 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.17644C>G	p.Arg5882Gly	missense	Exon 112 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.17644C>G	p.Arg5882Gly	missense	Exon 112 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.17644C>G	p.Arg5882Gly	missense	Exon 112 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.17644C>G	p.Arg5882Gly	missense	Exon 112 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.17644C>G	p.Arg5882Gly	missense	Exon 112 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.12541C>G	p.Arg4181Gly	missense	Exon 85 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248420 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460816 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726754

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111268

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.51
MutPred		0.75		Loss of MoRF binding (P = 0.0547)
MVP		0.62
MPC		0.35
ClinPred		0.96	D
GERP RS		3.2
Varity_R		0.37
gMVP		0.82
Mutation Taster		=71/29	polymorphism

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: rs769673154; hg19: chr2-152424922;