2-151497662-C-T

Variant names:

• chr2-151497662-C-T
• rs144709880
• NM_001164507.2:c.24264G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.24264G>A​(p.Met8088Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000789 in 1,585,128 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M8088V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16
• Publications: 3 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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-151497662-C-T is Benign according to our data. Variant chr2-151497662-C-T is described in ClinVar as Benign. ClinVar VariationId is 388062.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 = 0.00406 (618/152184) while in subpopulation AFR AF = 0.014 (579/41502). AF 95% confidence interval is 0.013. There are 9 homozygotes in GnomAd4. There are 292 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.24264G>A	p.Met8088Ile	missense	Exon 171 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24264G>A	p.Met8088Ile	missense	Exon 171 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24369G>A	p.Met8123Ile	missense	Exon 172 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.24264G>A	p.Met8088Ile	missense	Exon 171 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24264G>A	p.Met8088Ile	missense	Exon 171 of 182	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.579-124C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 614 AN: 152066 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00107 AC: 224 AN: 208676 AF XY: 0.000753

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000336

Gnomad OTH exome AF: 0.000375

GnomAD4 exome AF: 0.000442 AC: 633 AN: 1432944 Hom.: 2 Cov.: 32 AF XY: 0.000406 AC XY: 288 AN XY: 709760

African (AFR) AF: 0.0154 AC: 509 AN: 33122

American (AMR) AF: 0.000714 AC: 29 AN: 40614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 38984

South Asian (SAS) AF: 0.0000365 AC: 3 AN: 82246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51832

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.0000310 AC: 34 AN: 1095356

Other (OTH) AF: 0.000961 AC: 57 AN: 59302

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152184 Hom.: 9 Cov.: 32 AF XY: 0.00393 AC XY: 292 AN XY: 74388

African (AFR) AF: 0.0140 AC: 579 AN: 41502

American (AMR) AF: 0.00177 AC: 27 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00479

ESP6500AA AF: 0.0181 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 142

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.051
Sift	Benign	0.43	T
Sift4G	Benign	0.17	T
Vest4		0.35
MutPred		0.43		Loss of catalytic residue at V8084 (P = 0.0267)
MVP		0.51
MPC		0.061
ClinPred		0.012	T
GERP RS		2.6
gMVP		0.15
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: -36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144709880; hg19: chr2-152354176;