rs66961115

Variant names:

• chr2-178530827-G-A
• rs66961115
• NM_001267550.2:c.105788C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.105788C>T​(p.Ala35263Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,782 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35263F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 33)
  • Exomes 𝑓: 0.014 (165 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 1.52
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022972524).
• BP6: Variant 2-178530827-G-A is Benign according to our data. Variant chr2-178530827-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1567/152102) while in subpopulation NFE AF = 0.0155 (1056/68002). AF 95% confidence interval is 0.0148. There are 23 homozygotes in GnomAd4. There are 754 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.105788C>T	p.Ala35263Val	missense	Exon 358 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.100865C>T	p.Ala33622Val	missense	Exon 308 of 313	NP_001243779.1
	TTN	NM_133378.4		c.98084C>T	p.Ala32695Val	missense	Exon 307 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.105788C>T	p.Ala35263Val	missense	Exon 358 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.105632C>T	p.Ala35211Val	missense	Exon 356 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.105512C>T	p.Ala35171Val	missense	Exon 356 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1567 AN: 151984 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.0109 AC: 2724 AN: 249062 AF XY: 0.0107

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.00596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.00976

GnomAD4 exome AF: 0.0138 AC: 20216 AN: 1461680 Hom.: 165 Cov.: 33 AF XY: 0.0134 AC XY: 9777 AN XY: 727122

African (AFR) AF: 0.00173 AC: 58 AN: 33478

American (AMR) AF: 0.00472 AC: 211 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00647 AC: 169 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00133 AC: 115 AN: 86256

European-Finnish (FIN) AF: 0.0246 AC: 1312 AN: 53398

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.0158 AC: 17616 AN: 1111850

Other (OTH) AF: 0.0115 AC: 695 AN: 60374

GnomAD4 genome AF: 0.0103 AC: 1567 AN: 152102 Hom.: 23 Cov.: 33 AF XY: 0.0101 AC XY: 754 AN XY: 74336

African (AFR) AF: 0.00251 AC: 104 AN: 41500

American (AMR) AF: 0.00687 AC: 105 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.0238 AC: 251 AN: 10550

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1056 AN: 68002

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00516 Hom.: 12

Bravo AF: 0.00868

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00210 AC: 8

ESP6500EA AF: 0.0143 AC: 118

ExAC AF: 0.0114 AC: 1377

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0148

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.9
DANN	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.072
Sift	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.077
MPC		0.083
ClinPred		0.0080	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=97/3	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: rs66961115; hg19: chr2-179395554;