rs202040332

Variant names:

• chr2-178560726-G-C
• rs202040332
• NM_001267550.2:c.85406C>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.85406C>G​(p.Ser28469Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000877 in 1,613,708 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: 5.24
• Publications: 10 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=0.008784324).
• BP6: Variant 2-178560726-G-C is Benign according to our data. Variant chr2-178560726-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47446.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00144 (219/152290) while in subpopulation EAS AF = 0.00368 (19/5170). AF 95% confidence interval is 0.00241. There are 2 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.85406C>G	p.Ser28469Cys	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.80483C>G	p.Ser26828Cys	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.77702C>G	p.Ser25901Cys	missense	Exon 275 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.85406C>G	p.Ser28469Cys	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.85250C>G	p.Ser28417Cys	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.85130C>G	p.Ser28377Cys	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00215 AC: 534 AN: 248440 AF XY: 0.00217

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00538

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.000364

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.000818 AC: 1196 AN: 1461418 Hom.: 6 Cov.: 32 AF XY: 0.000794 AC XY: 577 AN XY: 726992

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26130

East Asian (EAS) AF: 0.00273 AC: 108 AN: 39606

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86250

European-Finnish (FIN) AF: 0.0146 AC: 777 AN: 53346

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

European-Non Finnish (NFE) AF: 0.000183 AC: 203 AN: 1111782

Other (OTH) AF: 0.000928 AC: 56 AN: 60360

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152290 Hom.: 2 Cov.: 33 AF XY: 0.00231 AC XY: 172 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00368 AC: 19 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000340 Hom.: 1

Bravo AF: 0.000487

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00166 AC: 200

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	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	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.82
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.2
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.27
Sift	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.35
MVP		0.35
MPC		0.41
ClinPred		0.072	T
GERP RS		6.0
Mutation Taster		=98/2	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: rs202040332; hg19: chr2-179425453; COSMIC: COSV60337621; COSMIC: COSV60337621;