rs34800215

Variant names:

• chr2-151671122-C-G
• rs34800215
• NM_001164507.2:c.4407G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-151671122-C-G
• chr2-151671122-C-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.4407G>C​(p.Glu1469Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,902 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (93 hom., cov: 32)
  • Exomes 𝑓: 0.018 (335 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0400
• Publications: 15 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 (MetaRNN=0.0029376447).
• BP6: Variant 2-151671122-C-G is Benign according to our data. Variant chr2-151671122-C-G is described in ClinVar as Benign. ClinVar VariationId is 129743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 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.4407G>C	p.Glu1469Asp	missense	Exon 38 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.4407G>C	p.Glu1469Asp	missense	Exon 38 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.4407G>C	p.Glu1469Asp	missense	Exon 38 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.4407G>C	p.Glu1469Asp	missense	Exon 38 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.4407G>C	p.Glu1469Asp	missense	Exon 38 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.4407G>C	p.Glu1469Asp	missense	Exon 38 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4165 AN: 152168 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0197 AC: 4922 AN: 249252 AF XY: 0.0203

Gnomad AFR exome AF: 0.0555

Gnomad AMR exome AF: 0.00872

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.00417

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0184 AC: 26966 AN: 1461616 Hom.: 335 Cov.: 33 AF XY: 0.0188 AC XY: 13699 AN XY: 727102

African (AFR) AF: 0.0527 AC: 1763 AN: 33476

American (AMR) AF: 0.00966 AC: 432 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1227 AN: 26136

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39700

South Asian (SAS) AF: 0.0305 AC: 2627 AN: 86246

European-Finnish (FIN) AF: 0.0123 AC: 658 AN: 53400

Middle Eastern (MID) AF: 0.0253 AC: 146 AN: 5768

European-Non Finnish (NFE) AF: 0.0167 AC: 18599 AN: 1111796

Other (OTH) AF: 0.0239 AC: 1441 AN: 60370

GnomAD4 genome AF: 0.0274 AC: 4176 AN: 152286 Hom.: 93 Cov.: 32 AF XY: 0.0266 AC XY: 1981 AN XY: 74460

African (AFR) AF: 0.0535 AC: 2225 AN: 41564

American (AMR) AF: 0.0167 AC: 255 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5178

South Asian (SAS) AF: 0.0249 AC: 120 AN: 4818

European-Finnish (FIN) AF: 0.0121 AC: 129 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1187 AN: 68028

Other (OTH) AF: 0.0261 AC: 55 AN: 2110

Alfa AF: 0.0178 Hom.: 23

Bravo AF: 0.0285

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.0479 AC: 198

ESP6500EA AF: 0.0188 AC: 158

ExAC AF: 0.0201 AC: 2427

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0202

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Nemaline myopathy 2 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.040
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.093
Sift	Benign	0.40	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.24		Loss of helix (P = 0.1299)
MPC		0.33
ClinPred		0.024	T
GERP RS		3.6
Varity_R		0.14
gMVP		0.42
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: rs34800215; hg19: chr2-152527636; COSMIC: COSV51417601;