2-151642841-T-C

Variant names:

• chr2-151642841-T-C
• rs76767949
• NM_001164507.2:c.8189A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.8189A>G​(p.Asp2730Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00316 in 1,612,288 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2730E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (115 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.10
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005199045).
• BP6: Variant 2-151642841-T-C is Benign according to our data. Variant chr2-151642841-T-C is described in ClinVar as Benign. ClinVar VariationId is 129757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

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.8189A>G	p.Asp2730Gly	missense	Exon 59 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.8189A>G	p.Asp2730Gly	missense	Exon 59 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.8189A>G	p.Asp2730Gly	missense	Exon 59 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.8189A>G	p.Asp2730Gly	missense	Exon 59 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.8189A>G	p.Asp2730Gly	missense	Exon 59 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.8189A>G	p.Asp2730Gly	missense	Exon 59 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 634 AN: 152214 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0714

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00892 AC: 2195 AN: 245966 AF XY: 0.00830

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0800

Gnomad FIN exome AF: 0.00662

Gnomad NFE exome AF: 0.000684

Gnomad OTH exome AF: 0.00552

GnomAD4 exome AF: 0.00305 AC: 4460 AN: 1459956 Hom.: 115 Cov.: 31 AF XY: 0.00301 AC XY: 2183 AN XY: 726138

African (AFR) AF: 0.000179 AC: 6 AN: 33462

American (AMR) AF: 0.0122 AC: 543 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0665 AC: 2633 AN: 39598

South Asian (SAS) AF: 0.00232 AC: 199 AN: 85932

European-Finnish (FIN) AF: 0.00791 AC: 422 AN: 53346

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5716

European-Non Finnish (NFE) AF: 0.000266 AC: 295 AN: 1110932

Other (OTH) AF: 0.00597 AC: 360 AN: 60328

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152332 Hom.: 14 Cov.: 33 AF XY: 0.00460 AC XY: 343 AN XY: 74492

African (AFR) AF: 0.000529 AC: 22 AN: 41584

American (AMR) AF: 0.00627 AC: 96 AN: 15310

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

East Asian (EAS) AF: 0.0710 AC: 368 AN: 5184

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4824

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68014

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00221 Hom.: 31

Bravo AF: 0.00455

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000273 AC: 1

ESP6500EA AF: 0.000490 AC: 4

ExAC AF: 0.00826 AC: 998

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Nemaline myopathy 2 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.1
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.54
MVP		0.67
MPC		0.38
ClinPred		0.049	T
GERP RS		6.0
Varity_R		0.34
gMVP		0.54
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs76767949; hg19: chr2-152499355; COSMIC: COSV50873858;