rs118191309

Variant names:

• chr2-151506216-T-G
• rs118191309
• NM_001164507.2:c.23599A>C

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.23599A>C​(p.Lys7867Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,806 control chromosomes in the GnomAD database, including 38 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 (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0023 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (30 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.90
• 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]

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=0.004918307).
• BP6: Variant 2-151506216-T-G is Benign according to our data. Variant chr2-151506216-T-G is described in ClinVar as Benign. ClinVar VariationId is 194308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00225 (343/152370) while in subpopulation EAS AF = 0.0442 (229/5182). AF 95% confidence interval is 0.0395. There are 8 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.23599A>C	p.Lys7867Gln	missense	Exon 164 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23599A>C	p.Lys7867Gln	missense	Exon 164 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23704A>C	p.Lys7902Gln	missense	Exon 165 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.23599A>C	p.Lys7867Gln	missense	Exon 164 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23599A>C	p.Lys7867Gln	missense	Exon 164 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18496A>C	p.Lys6166Gln	missense	Exon 137 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152252 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00526 AC: 1311 AN: 249152 AF XY: 0.00484

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0473

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00155 AC: 2266 AN: 1461436 Hom.: 30 Cov.: 30 AF XY: 0.00148 AC XY: 1074 AN XY: 727014

African (AFR) AF: 0.000359 AC: 12 AN: 33472

American (AMR) AF: 0.00932 AC: 417 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0307 AC: 1217 AN: 39690

South Asian (SAS) AF: 0.00187 AC: 161 AN: 86244

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1111642

Other (OTH) AF: 0.00388 AC: 234 AN: 60360

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152370 Hom.: 8 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74520

African (AFR) AF: 0.000505 AC: 21 AN: 41584

American (AMR) AF: 0.00385 AC: 59 AN: 15306

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

East Asian (EAS) AF: 0.0442 AC: 229 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68042

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000939 Hom.: 2

Bravo AF: 0.00309

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00478 AC: 578

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Nemaline myopathy 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.082
Sift	Benign	0.28	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.27
MVP		0.43
MPC		0.075
ClinPred		0.011	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.23
Mutation Taster		=287/13	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: rs118191309; hg19: chr2-152362730; COSMIC: COSV108770098;