2-178581939-C-T

Variant names:

• chr2-178581939-C-T
• rs183276016
• NM_001267550.2:c.66430G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.66430G>A​(p.Ala22144Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22144S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 2.25
• Publications: 7 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.076449275).
• BP6: Variant 2-178581939-C-T is Benign according to our data. Variant chr2-178581939-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238827.

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.66430G>A	p.Ala22144Thr	missense	Exon 315 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.61507G>A	p.Ala20503Thr	missense	Exon 265 of 313	NP_001243779.1
	TTN	NM_133378.4		c.58726G>A	p.Ala19576Thr	missense	Exon 264 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.66430G>A	p.Ala22144Thr	missense	Exon 315 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.66274G>A	p.Ala22092Thr	missense	Exon 313 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.66154G>A	p.Ala22052Thr	missense	Exon 313 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000274 AC: 68 AN: 248372 AF XY: 0.000282

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000400

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000487 AC: 711 AN: 1460988 Hom.: 0 Cov.: 32 AF XY: 0.000482 AC XY: 350 AN XY: 726772

African (AFR) AF: 0.000209 AC: 7 AN: 33426

American (AMR) AF: 0.000537 AC: 24 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39566

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000590 AC: 656 AN: 1111484

Other (OTH) AF: 0.000348 AC: 21 AN: 60328

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74258

African (AFR) AF: 0.000217 AC: 9 AN: 41432

American (AMR) AF: 0.000524 AC: 8 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67988

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000397 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	2	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.95
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Benign	0.10	T
Polyphen		0.61	P
Vest4		0.26
MVP		0.22
MPC		0.10
ClinPred		0.026	T
GERP RS		5.6
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs183276016; hg19: chr2-179446666;