chr2-151710447-T-C

Variant names:

• chr2-151710447-T-C
• rs36105240
• NM_001164507.2:c.914A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.914A>G​(p.Asp305Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,611,260 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D305D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (35 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.75
• Publications: 6 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

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-151710447-T-C is Benign according to our data. Variant chr2-151710447-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00188 (286/152314) while in subpopulation EAS AF = 0.0232 (120/5178). AF 95% confidence interval is 0.0198. There are 4 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.914A>G	p.Asp305Gly	missense	Exon 11 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.914A>G	p.Asp305Gly	missense	Exon 11 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.914A>G	p.Asp305Gly	missense	Exon 11 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.914A>G	p.Asp305Gly	missense	Exon 11 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.914A>G	p.Asp305Gly	missense	Exon 11 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.914A>G	p.Asp305Gly	missense	Exon 11 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152196 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00321 AC: 798 AN: 248910 AF XY: 0.00294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0191

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00170 AC: 2474 AN: 1458946 Hom.: 35 Cov.: 29 AF XY: 0.00165 AC XY: 1196 AN XY: 725936

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 61 AN: 26082

East Asian (EAS) AF: 0.0338 AC: 1343 AN: 39676

South Asian (SAS) AF: 0.000349 AC: 30 AN: 86078

European-Finnish (FIN) AF: 0.0108 AC: 574 AN: 53326

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.000297 AC: 330 AN: 1109664

Other (OTH) AF: 0.00219 AC: 132 AN: 60264

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152314 Hom.: 4 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000990 Hom.: 4

Bravo AF: 0.00100

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.00348 AC: 421

Asia WGS AF: 0.0100 AC: 37 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Nemaline myopathy 2 (5)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.078
Sift	Benign	0.20	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.032	B
Vest4		0.46
MVP		0.34
MPC		0.14
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.16
gMVP		0.49
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs36105240; hg19: chr2-152566961;