rs769673154

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-151568408-G-A
• chr2-151568408-G-C
• chr2-151568408-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001164508.2(NEB):​c.17644C>T​(p.Arg5882Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,573,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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: 𝑓 0.0000089 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 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.

• BP6: Variant 2-151568408-G-A is Benign according to our data. Variant chr2-151568408-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447754.

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.17644C>T	p.Arg5882Trp	missense	Exon 112 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.17644C>T	p.Arg5882Trp	missense	Exon 112 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.17644C>T	p.Arg5882Trp	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>T	p.Arg5882Trp	missense	Exon 112 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.17644C>T	p.Arg5882Trp	missense	Exon 112 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.12541C>T	p.Arg4181Trp	missense	Exon 85 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112340 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000282 AC: 7 AN: 248420 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460816 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726754

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111268

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

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112340 Hom.: 0 Cov.: 31 AF XY: 0.0000185 AC XY: 1 AN XY: 53978

African (AFR) AF: 0.00 AC: 0 AN: 30872

American (AMR) AF: 0.000108 AC: 1 AN: 9220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2968

East Asian (EAS) AF: 0.00 AC: 0 AN: 3278

South Asian (SAS) AF: 0.00 AC: 0 AN: 3634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52500

Other (OTH) AF: 0.00 AC: 0 AN: 1444

Alfa AF: 0.0000480 Hom.: 0

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Nemaline myopathy 2 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.75		Loss of ubiquitination at K4182 (P = 0.0508)
MVP		0.71
MPC		0.35
ClinPred		0.92	D
GERP RS		3.2
Varity_R		0.39
gMVP		0.81
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; COSMIC: COSV99429300;