rs6433569

Variant names:

• chr2-151695548-A-C
• rs6433569
• NM_001164507.2:c.1674+30T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151695548-A-C
• chr2-151695548-A-G
• chr2-151695548-A-T

Variant summary

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

The NM_001164507.2(NEB):​c.1674+30T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,526,238 control chromosomes in the GnomAD database, including 468,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (35798 hom., cov: 32)
  • Exomes 𝑓: 0.78 (432730 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.152
• Publications: 12 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 (BayesDel_noAF=-0.86).
• BP6: Variant 2-151695548-A-C is Benign according to our data. Variant chr2-151695548-A-C is described in ClinVar as Benign. ClinVar VariationId is 257767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.1674+30T>G		intron_variant	Intron 18 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.1674+30T>G		intron_variant	Intron 18 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.1674+30T>G		intron_variant	Intron 18 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.1674+30T>G		intron_variant	Intron 18 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000489048.1	n.573+30T>G		intron_variant	Intron 6 of 11	1
NEB	ENST00000409198.5	c.1674+30T>G		intron_variant	Intron 18 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95503 AN: 152034 Hom.: 35795 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.822

Gnomad OTH AF: 0.679

GnomAD2 exomes AF: 0.733 AC: 175634 AN: 239766 AF XY: 0.737

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.849

Gnomad ASJ exome AF: 0.734

Gnomad EAS exome AF: 0.412

Gnomad FIN exome AF: 0.851

Gnomad NFE exome AF: 0.824

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.783 AC: 1075274 AN: 1374086 Hom.: 432730 Cov.: 20 AF XY: 0.780 AC XY: 536378 AN XY: 687496

African (AFR) AF: 0.186 AC: 5843 AN: 31388

American (AMR) AF: 0.840 AC: 36127 AN: 43022

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 18748 AN: 25500

East Asian (EAS) AF: 0.385 AC: 15035 AN: 39060

South Asian (SAS) AF: 0.646 AC: 53090 AN: 82168

European-Finnish (FIN) AF: 0.849 AC: 45157 AN: 53218

Middle Eastern (MID) AF: 0.751 AC: 4214 AN: 5608

European-Non Finnish (NFE) AF: 0.824 AC: 854656 AN: 1036628

Other (OTH) AF: 0.738 AC: 42404 AN: 57494

GnomAD4 genome AF: 0.628 AC: 95499 AN: 152152 Hom.: 35798 Cov.: 32 AF XY: 0.633 AC XY: 47053 AN XY: 74386

African (AFR) AF: 0.205 AC: 8515 AN: 41488

American (AMR) AF: 0.783 AC: 11972 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 2518 AN: 3470

East Asian (EAS) AF: 0.394 AC: 2038 AN: 5176

South Asian (SAS) AF: 0.641 AC: 3093 AN: 4822

European-Finnish (FIN) AF: 0.859 AC: 9092 AN: 10588

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.822 AC: 55897 AN: 68004

Other (OTH) AF: 0.671 AC: 1415 AN: 2110

Alfa AF: 0.632 Hom.: 7343

Bravo AF: 0.605

Asia WGS AF: 0.446 AC: 1553 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nemaline myopathy 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.8
DANN	Benign	0.58
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs6433569; hg19: chr2-152552062; COSMIC: COSV50869589;