NM_001267550.2:c.99946G>A

Variant names:

• chr2-178537163-C-T
• rs374295768
• NM_001267550.2:c.99946G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.99946G>A​(p.Ala33316Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,608 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 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 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.18
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010286748).
• BP6: Variant 2-178537163-C-T is Benign according to our data. Variant chr2-178537163-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203051.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.99946G>A	p.Ala33316Thr	missense	Exon 356 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.95023G>A	p.Ala31675Thr	missense	Exon 306 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.92242G>A	p.Ala30748Thr	missense	Exon 305 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.99946G>A	p.Ala33316Thr	missense	Exon 356 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.99790G>A	p.Ala33264Thr	missense	Exon 354 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.99670G>A	p.Ala33224Thr	missense	Exon 354 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000274 AC: 68 AN: 248192 AF XY: 0.000319

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461350 Hom.: 4 Cov.: 32 AF XY: 0.000166 AC XY: 121 AN XY: 726966

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.0000895 AC: 4 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111694

Other (OTH) AF: 0.000166 AC: 10 AN: 60350

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74440

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

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

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000257 AC: 31

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.0
DANN	Benign	0.95
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.18	N
PhyloP100		2.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.042
Sift	Benign	0.44	T
Polyphen		0.0040	B
Vest4		0.25
MVP		0.13
MPC		0.081
ClinPred		0.012	T
GERP RS		3.5
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: rs374295768; hg19: chr2-179401890; COSMIC: COSV60081504; COSMIC: COSV60081504;