rs536508687

Variant names:

• chr2-151579592-C-T
• rs536508687
• NM_001164507.2:c.16450G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164507.2(NEB):​c.16450G>A​(p.Ala5484Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (242 hom., cov: 9)
  • Exomes 𝑓: 0.065 (4599 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.961
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015130043).
• BP6: Variant 2-151579592-C-T is Benign according to our data. Variant chr2-151579592-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.16450G>A	p.Ala5484Thr	missense	Exon 105 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.16450G>A	p.Ala5484Thr	missense	Exon 105 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.16450G>A	p.Ala5484Thr	missense	Exon 105 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.16450G>A	p.Ala5484Thr	missense	Exon 105 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16450G>A	p.Ala5484Thr	missense	Exon 105 of 182	ENSP00000416578.2
	NEB	ENST00000413693.5	TSL:5	c.640G>A	p.Ala214Thr	missense	Exon 5 of 74	ENSP00000410961.1

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 4279 AN: 64334 Hom.: 242 Cov.: 9

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0556

Gnomad NFE AF: 0.0782

Gnomad OTH AF: 0.0657

GnomAD2 exomes AF: 0.0665 AC: 2624 AN: 39442 AF XY: 0.0650

Gnomad AFR exome AF: 0.0604

Gnomad AMR exome AF: 0.0622

Gnomad ASJ exome AF: 0.0850

Gnomad EAS exome AF: 0.0222

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.0765

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0648 AC: 71144 AN: 1098712 Hom.: 4599 Cov.: 16 AF XY: 0.0635 AC XY: 35035 AN XY: 551350

African (AFR) AF: 0.0530 AC: 1491 AN: 28114

American (AMR) AF: 0.0325 AC: 1139 AN: 35060

Ashkenazi Jewish (ASJ) AF: 0.0758 AC: 1796 AN: 23708

East Asian (EAS) AF: 0.0305 AC: 1043 AN: 34248

South Asian (SAS) AF: 0.0430 AC: 3217 AN: 74762

European-Finnish (FIN) AF: 0.0801 AC: 3791 AN: 47340

Middle Eastern (MID) AF: 0.0465 AC: 169 AN: 3636

European-Non Finnish (NFE) AF: 0.0692 AC: 55588 AN: 803458

Other (OTH) AF: 0.0601 AC: 2910 AN: 48386

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0665 AC: 4285 AN: 64458 Hom.: 242 Cov.: 9 AF XY: 0.0660 AC XY: 1954 AN XY: 29602

African (AFR) AF: 0.0526 AC: 1223 AN: 23248

American (AMR) AF: 0.0612 AC: 253 AN: 4134

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 183 AN: 1978

East Asian (EAS) AF: 0.0276 AC: 54 AN: 1956

South Asian (SAS) AF: 0.0402 AC: 71 AN: 1768

European-Finnish (FIN) AF: 0.109 AC: 296 AN: 2704

Middle Eastern (MID) AF: 0.0513 AC: 8 AN: 156

European-Non Finnish (NFE) AF: 0.0782 AC: 2129 AN: 27210

Other (OTH) AF: 0.0662 AC: 51 AN: 770

Alfa AF: 0.0565 Hom.: 83

ExAC AF: 0.0599 AC: 186

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.96
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.036
Sift	Benign	0.036	D
Sift4G	Uncertain	0.027	D
Vest4		0.14
MPC		0.34
ClinPred		0.012	T
GERP RS		4.7
gMVP		0.0016
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs536508687; hg19: chr2-152436106; COSMIC: COSV50816930;