rs35654397

Variant names:

• chr2-151672396-C-G
• rs35654397
• NM_001164507.2:c.4272G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-151672396-C-G
• chr2-151672396-C-T

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.4272G>C​(p.Thr1424Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,605,236 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1424T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (18 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -2.38
• Publications: 2 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 (BayesDel_noAF=-0.81).
• BP6: Variant 2-151672396-C-G is Benign according to our data. Variant chr2-151672396-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197008.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00254 (386/152258) while in subpopulation NFE AF = 0.00376 (256/68018). AF 95% confidence interval is 0.00339. There are 0 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.4272G>C	p.Thr1424Thr	synonymous	Exon 37 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.4272G>C	p.Thr1424Thr	synonymous	Exon 37 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.4272G>C	p.Thr1424Thr	synonymous	Exon 37 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.4272G>C	p.Thr1424Thr	synonymous	Exon 37 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.4272G>C	p.Thr1424Thr	synonymous	Exon 37 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.4272G>C	p.Thr1424Thr	synonymous	Exon 37 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00200 AC: 492 AN: 246266 AF XY: 0.00214

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.000843

Gnomad ASJ exome AF: 0.000927

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00174

Gnomad NFE exome AF: 0.00312

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00351 AC: 5096 AN: 1452978 Hom.: 18 Cov.: 31 AF XY: 0.00346 AC XY: 2492 AN XY: 721206

African (AFR) AF: 0.000690 AC: 23 AN: 33330

American (AMR) AF: 0.000965 AC: 43 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 30 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00181 AC: 155 AN: 85496

European-Finnish (FIN) AF: 0.00167 AC: 89 AN: 53158

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5730

European-Non Finnish (NFE) AF: 0.00411 AC: 4544 AN: 1105416

Other (OTH) AF: 0.00343 AC: 206 AN: 60030

GnomAD4 genome AF: 0.00254 AC: 386 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74458

African (AFR) AF: 0.000650 AC: 27 AN: 41540

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00376 AC: 256 AN: 68018

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00255

EpiCase AF: 0.00406

EpiControl AF: 0.00381

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	2	Nemaline myopathy 2 (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.081
DANN	Benign	0.33
PhyloP100		-2.4
Mutation Taster		=98/2	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: rs35654397; hg19: chr2-152528910;