chr2-151506970-G-A

Variant names:

• chr2-151506970-G-A
• rs34368668
• NM_001164507.2:c.23495C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.23495C>T​(p.Thr7832Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00212 in 1,611,056 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.61
• Publications: 6 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067389607).
• BP6: Variant 2-151506970-G-A is Benign according to our data. Variant chr2-151506970-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1580/152256) while in subpopulation AFR AF = 0.0361 (1500/41544). AF 95% confidence interval is 0.0346. There are 27 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.23495C>T	p.Thr7832Ile	missense	Exon 163 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23495C>T	p.Thr7832Ile	missense	Exon 163 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23600C>T	p.Thr7867Ile	missense	Exon 164 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.23495C>T	p.Thr7832Ile	missense	Exon 163 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23495C>T	p.Thr7832Ile	missense	Exon 163 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18392C>T	p.Thr6131Ile	missense	Exon 136 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1577 AN: 152138 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00281 AC: 700 AN: 248736 AF XY: 0.00233

Gnomad AFR exome AF: 0.0373

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00126 AC: 1838 AN: 1458800 Hom.: 33 Cov.: 29 AF XY: 0.00108 AC XY: 785 AN XY: 725872

African (AFR) AF: 0.0395 AC: 1318 AN: 33370

American (AMR) AF: 0.00237 AC: 106 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00280 AC: 73 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00219 AC: 12 AN: 5488

European-Non Finnish (NFE) AF: 0.000167 AC: 185 AN: 1110092

Other (OTH) AF: 0.00234 AC: 141 AN: 60246

GnomAD4 genome AF: 0.0104 AC: 1580 AN: 152256 Hom.: 27 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74444

African (AFR) AF: 0.0361 AC: 1500 AN: 41544

American (AMR) AF: 0.00314 AC: 48 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68008

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00416 Hom.: 38

Bravo AF: 0.0120

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0339 AC: 123

ESP6500EA AF: 0.000861 AC: 7

ExAC AF: 0.00344 AC: 415

Asia WGS AF: 0.000867 AC: 3 AN: 3474

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Nemaline myopathy 2 (2)
-	-	2	not provided (2)
-	-	1	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.25
MVP		0.53
MPC		0.10
ClinPred		0.030	T
GERP RS		5.2
PromoterAI		-0.024	Neutral
Varity_R		0.27
gMVP		0.79
Mutation Taster		=87/13	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: rs34368668; hg19: chr2-152363484;