chr2-178589153-T-C

Variant names:

• chr2-178589153-T-C
• rs200689750
• NM_001267550.2:c.62572A>G

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.62572A>G​(p.Thr20858Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000565 in 1,613,320 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:12
• Conservation: PhyloP100: 6.08
• Publications: 8 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=0.059380352).
• BP6: Variant 2-178589153-T-C is Benign according to our data. Variant chr2-178589153-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47185.
• BS2: High Homozygotes in GnomAdExome4 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.62572A>G	p.Thr20858Ala	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.57649A>G	p.Thr19217Ala	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.54868A>G	p.Thr18290Ala	missense	Exon 253 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.62572A>G	p.Thr20858Ala	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.62416A>G	p.Thr20806Ala	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.62296A>G	p.Thr20766Ala	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000574

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000407 AC: 101 AN: 248280 AF XY: 0.000408

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000810

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000595 AC: 870 AN: 1461108 Hom.: 2 Cov.: 32 AF XY: 0.000586 AC XY: 426 AN XY: 726864

African (AFR) AF: 0.0000897 AC: 3 AN: 33458

American (AMR) AF: 0.0000671 AC: 3 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000749 AC: 833 AN: 1111650

Other (OTH) AF: 0.000315 AC: 19 AN: 60350

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74406

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000786 AC: 3

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.000422 AC: 51

EpiCase AF: 0.00109

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	6	not provided (9)
-	1	2	not specified (3)
-	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	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.84
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.059	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Benign	0.15	T
Polyphen		0.45	P
Vest4		0.38
MVP		0.45
MPC		0.18
ClinPred		0.053	T
GERP RS		5.9
Mutation Taster		=78/22	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: rs200689750; hg19: chr2-179453880;