2-151560595-G-A

Variant names:

• chr2-151560595-G-A
• rs16830216
• NM_001164507.2:c.19311C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001164508.2(NEB):​c.19311C>T​(p.Ser6437Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,608,496 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (23 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.61
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-151560595-G-A is Benign according to our data. Variant chr2-151560595-G-A is described in ClinVar as Benign. ClinVar VariationId is 129718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00837 (1275/152258) while in subpopulation AFR AF = 0.0291 (1209/41556). AF 95% confidence interval is 0.0277. There are 24 homozygotes in GnomAd4. There are 599 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.19311C>T	p.Ser6437Ser	synonymous	Exon 124 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.19311C>T	p.Ser6437Ser	synonymous	Exon 124 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.19311C>T	p.Ser6437Ser	synonymous	Exon 124 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.19311C>T	p.Ser6437Ser	synonymous	Exon 124 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19311C>T	p.Ser6437Ser	synonymous	Exon 124 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.14208C>T	p.Ser4736Ser	synonymous	Exon 97 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1266 AN: 152140 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00215 AC: 521 AN: 242320 AF XY: 0.00162

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000728

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.000847 AC: 1233 AN: 1456238 Hom.: 23 Cov.: 32 AF XY: 0.000727 AC XY: 526 AN XY: 723844

African (AFR) AF: 0.0301 AC: 1004 AN: 33362

American (AMR) AF: 0.00177 AC: 78 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5722

European-Non Finnish (NFE) AF: 0.0000433 AC: 48 AN: 1109236

Other (OTH) AF: 0.00153 AC: 92 AN: 60220

GnomAD4 genome AF: 0.00837 AC: 1275 AN: 152258 Hom.: 24 Cov.: 32 AF XY: 0.00805 AC XY: 599 AN XY: 74428

African (AFR) AF: 0.0291 AC: 1209 AN: 41556

American (AMR) AF: 0.00308 AC: 47 AN: 15280

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00439 Hom.: 8

Bravo AF: 0.00960

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		2.6
Mutation Taster		=55/45	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: rs16830216; hg19: chr2-152417109;