2-151526203-C-T

Variant names:

• chr2-151526203-C-T
• rs201400523
• NM_001164507.2:c.22005G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001164508.2(NEB):​c.22005G>A​(p.Thr7335Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,613,886 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T7335T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (8 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.742
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-151526203-C-T is Benign according to our data. Variant chr2-151526203-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194142.
• BP7: Synonymous conserved (PhyloP=-0.742 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000854 (130/152280) while in subpopulation SAS AF = 0.00477 (23/4818). AF 95% confidence interval is 0.00326. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.22005G>A	p.Thr7335Thr	synonymous	Exon 149 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.22005G>A	p.Thr7335Thr	synonymous	Exon 149 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.22110G>A	p.Thr7370Thr	synonymous	Exon 150 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.22005G>A	p.Thr7335Thr	synonymous	Exon 149 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.22005G>A	p.Thr7335Thr	synonymous	Exon 149 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.16902G>A	p.Thr5634Thr	synonymous	Exon 122 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00109 AC: 272 AN: 248808 AF XY: 0.00132

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000976

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000802 AC: 1172 AN: 1461606 Hom.: 8 Cov.: 32 AF XY: 0.000927 AC XY: 674 AN XY: 727076

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.000492 AC: 22 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39672

South Asian (SAS) AF: 0.00414 AC: 357 AN: 86252

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53396

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000639 AC: 710 AN: 1111818

Other (OTH) AF: 0.000729 AC: 44 AN: 60368

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74458

African (AFR) AF: 0.000217 AC: 9 AN: 41566

American (AMR) AF: 0.00203 AC: 31 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000763 Hom.: 0

Bravo AF: 0.000854

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00125

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.60
DANN	Benign	0.55
PhyloP100		-0.74
Mutation Taster		=99/1	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: rs201400523; hg19: chr2-152382717; COSMIC: COSV104384787; COSMIC: COSV104384787;