NM_001267550.2:c.90826T>G

Variant names:

• chr2-178552074-A-C
• rs150430592
• NM_001267550.2:c.90826T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.90826T>G​(p.Cys30276Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,718 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (44 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23
• Conservation: PhyloP100: 9.32
• Publications: 11 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008630365).
• BP6: Variant 2-178552074-A-C is Benign according to our data. Variant chr2-178552074-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47501.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00174 (265/152256) while in subpopulation SAS AF = 0.0234 (113/4822). AF 95% confidence interval is 0.0199. There are 5 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.90826T>G	p.Cys30276Gly	missense	Exon 335 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.85903T>G	p.Cys28635Gly	missense	Exon 285 of 313	NP_001243779.1
	TTN	NM_133378.4		c.83122T>G	p.Cys27708Gly	missense	Exon 284 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.90826T>G	p.Cys30276Gly	missense	Exon 335 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.90670T>G	p.Cys30224Gly	missense	Exon 333 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.90550T>G	p.Cys30184Gly	missense	Exon 333 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 152138 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00357 AC: 889 AN: 248684 AF XY: 0.00452

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00348

GnomAD4 exome AF: 0.00215 AC: 3135 AN: 1461462 Hom.: 44 Cov.: 33 AF XY: 0.00273 AC XY: 1988 AN XY: 726996

African (AFR) AF: 0.000299 AC: 10 AN: 33468

American (AMR) AF: 0.000671 AC: 30 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.0203 AC: 1748 AN: 86218

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53382

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5762

European-Non Finnish (NFE) AF: 0.00102 AC: 1132 AN: 1111736

Other (OTH) AF: 0.00270 AC: 163 AN: 60366

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152256 Hom.: 5 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74432

African (AFR) AF: 0.000168 AC: 7 AN: 41546

American (AMR) AF: 0.00170 AC: 26 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

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

South Asian (SAS) AF: 0.0234 AC: 113 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00160 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000492 AC: 2

ESP6500EA AF: 0.00190 AC: 16

ExAC AF: 0.00415 AC: 502

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00243

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	5	not provided (6)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.95
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.32	N
PhyloP100		9.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.81
MPC		0.52
ClinPred		0.15	T
GERP RS		5.8
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150430592; hg19: chr2-179416801;