rs199710125

Variant names:

• chr2-151696656-T-C
• rs199710125
• NM_001164507.2:c.1550A>G

Variant summary

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

The NM_001164508.2(NEB):​c.1550A>G​(p.Asn517Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000261 in 1,613,546 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 6.93
• Publications: 5 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

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-151696656-T-C is Benign according to our data. Variant chr2-151696656-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290878.

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.1550A>G	p.Asn517Ser	missense	Exon 17 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.1550A>G	p.Asn517Ser	missense	Exon 17 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.1550A>G	p.Asn517Ser	missense	Exon 17 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.1550A>G	p.Asn517Ser	missense	Exon 17 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.1550A>G	p.Asn517Ser	missense	Exon 17 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000489048.1	TSL:1	n.449A>G		non_coding_transcript_exon	Exon 5 of 12

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249224 AF XY: 0.0000961

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000275 AC: 402 AN: 1461342 Hom.: 1 Cov.: 30 AF XY: 0.000260 AC XY: 189 AN XY: 726962

African (AFR) AF: 0.000120 AC: 4 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000345 AC: 383 AN: 1111580

Other (OTH) AF: 0.000149 AC: 9 AN: 60360

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Nemaline myopathy 2 (2)
-	1	1	not provided (2)
-	1	-	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.30
Sift	Benign	0.089	T
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.54
MVP		0.65
MPC		0.31
ClinPred		0.22	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.25
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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: rs199710125; hg19: chr2-152553170;