rs75639119

Variant names:

• chr2-151627801-C-T
• rs75639119
• NM_001164507.2:c.9865G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164508.2(NEB):​c.9865G>A​(p.Gly3289Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00368 in 1,613,768 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts 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. G3289D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (28 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 6.03
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009073287).
• BP6: Variant 2-151627801-C-T is Benign according to our data. Variant chr2-151627801-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95141.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00429 (653/152108) while in subpopulation NFE AF = 0.00404 (275/67996). AF 95% confidence interval is 0.00365. There are 8 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.9865G>A	p.Gly3289Ser	missense	Exon 69 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.9865G>A	p.Gly3289Ser	missense	Exon 69 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.9865G>A	p.Gly3289Ser	missense	Exon 69 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.9865G>A	p.Gly3289Ser	missense	Exon 69 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9865G>A	p.Gly3289Ser	missense	Exon 69 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.9136G>A	p.Gly3046Ser	missense	Exon 66 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 653 AN: 151990 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00407 AC: 1013 AN: 249108 AF XY: 0.00411

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00361 AC: 5283 AN: 1461660 Hom.: 28 Cov.: 32 AF XY: 0.00354 AC XY: 2577 AN XY: 727116

African (AFR) AF: 0.000568 AC: 19 AN: 33478

American (AMR) AF: 0.000581 AC: 26 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000904 AC: 78 AN: 86256

European-Finnish (FIN) AF: 0.0221 AC: 1179 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00345 AC: 3833 AN: 1111828

Other (OTH) AF: 0.00232 AC: 140 AN: 60374

GnomAD4 genome AF: 0.00429 AC: 653 AN: 152108 Hom.: 8 Cov.: 32 AF XY: 0.00546 AC XY: 406 AN XY: 74330

African (AFR) AF: 0.000554 AC: 23 AN: 41498

American (AMR) AF: 0.000327 AC: 5 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4810

European-Finnish (FIN) AF: 0.0304 AC: 321 AN: 10564

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

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 67996

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00286 Hom.: 0

Bravo AF: 0.00218

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.00402 AC: 33

ExAC AF: 0.00347 AC: 419

EpiCase AF: 0.00365

EpiControl AF: 0.00208

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	2	1	Nemaline myopathy 2 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.64
MPC		0.34
ClinPred		0.14	T
GERP RS		5.6
Varity_R		0.29
gMVP		0.51
Mutation Taster		=90/10	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: rs75639119; hg19: chr2-152484315; COSMIC: COSV50864996;