rs4364020

Variant names:

• chr2-151561167-G-A
• rs4364020
• NM_001164507.2:c.19101+41C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151561167-G-A
• chr2-151561167-G-T

Variant summary

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

The NM_001164508.2(NEB):​c.19101+41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,573,978 control chromosomes in the GnomAD database, including 1,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (647 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1225 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0660
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-151561167-G-A is Benign according to our data. Variant chr2-151561167-G-A is described in ClinVar as Benign. ClinVar VariationId is 257777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

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.19101+41C>T		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.19101+41C>T		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.19101+41C>T		intron	N/A	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.19101+41C>T		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19101+41C>T		intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.13998+41C>T		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8355 AN: 152066 Hom.: 635 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.0517

GnomAD2 exomes AF: 0.0336 AC: 7473 AN: 222124 AF XY: 0.0333

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0325

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0151 AC: 21531 AN: 1421794 Hom.: 1225 Cov.: 27 AF XY: 0.0163 AC XY: 11554 AN XY: 707032

African (AFR) AF: 0.167 AC: 5453 AN: 32634

American (AMR) AF: 0.0110 AC: 464 AN: 41998

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 829 AN: 25540

East Asian (EAS) AF: 0.139 AC: 5434 AN: 39122

South Asian (SAS) AF: 0.0679 AC: 5678 AN: 83616

European-Finnish (FIN) AF: 0.000344 AC: 18 AN: 52338

Middle Eastern (MID) AF: 0.0196 AC: 111 AN: 5658

European-Non Finnish (NFE) AF: 0.00167 AC: 1802 AN: 1081906

Other (OTH) AF: 0.0295 AC: 1742 AN: 58982

GnomAD4 genome AF: 0.0552 AC: 8398 AN: 152184 Hom.: 647 Cov.: 32 AF XY: 0.0552 AC XY: 4108 AN XY: 74416

African (AFR) AF: 0.157 AC: 6519 AN: 41488

American (AMR) AF: 0.0231 AC: 353 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.146 AC: 755 AN: 5176

South Asian (SAS) AF: 0.0774 AC: 373 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68004

Other (OTH) AF: 0.0611 AC: 129 AN: 2110

Alfa AF: 0.0175 Hom.: 58

Bravo AF: 0.0613

Asia WGS AF: 0.139 AC: 482 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.28
DANN	Benign	0.54
PhyloP100		-0.066
Mutation Taster		=100/0	polymorphism (auto)

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: rs4364020; hg19: chr2-152417681; COSMIC: COSV51419733;