2-151633716-T-A

Variant names:

• chr2-151633716-T-A
• rs543100735
• NM_001164507.2:c.9352A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_001271208.2(NEB):​c.9352A>T​(p.Thr3118Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. 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. T3118A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: NEB NM_001271208.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.98
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30179924).
• BP6: Variant 2-151633716-T-A is Benign according to our data. Variant chr2-151633716-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257840.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. 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.9352A>T	p.Thr3118Ser	missense	Exon 65 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.9352A>T	p.Thr3118Ser	missense	Exon 65 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.9352A>T	p.Thr3118Ser	missense	Exon 65 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.9352A>T	p.Thr3118Ser	missense	Exon 65 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9352A>T	p.Thr3118Ser	missense	Exon 65 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.8854-2538A>T		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000136 AC: 34 AN: 249112 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1461700 Hom.: 0 Cov.: 114 AF XY: 0.000144 AC XY: 105 AN XY: 727134

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000174 AC: 193 AN: 1111864

Other (OTH) AF: 0.0000828 AC: 5 AN: 60372

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74480

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.47	T
PhyloP100		5.0
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.041	D
Sift4G	Uncertain	0.017	D
Vest4		0.51
MutPred		0.35		Gain of disorder (P = 0.1061)
MVP		0.56
MPC		0.22
ClinPred		0.11	T
GERP RS		5.9
gMVP		0.029
Mutation Taster		=86/14	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: rs543100735; hg19: chr2-152490230;