2-178592871-C-T

Variant names:

• chr2-178592871-C-T
• rs200732032
• NM_001267550.2:c.59248G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_001267550.2(TTN):​c.59248G>A​(p.Gly19750Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,613,304 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. G19750C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:6
• Conservation: PhyloP100: 7.86
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39618886).
• BP6: Variant 2-178592871-C-T is Benign according to our data. Variant chr2-178592871-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130675.

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.59248G>A	p.Gly19750Ser	missense	Exon 300 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.54325G>A	p.Gly18109Ser	missense	Exon 250 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.51544G>A	p.Gly17182Ser	missense	Exon 249 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.59248G>A	p.Gly19750Ser	missense	Exon 300 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.59092G>A	p.Gly19698Ser	missense	Exon 298 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.58972G>A	p.Gly19658Ser	missense	Exon 298 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 248654 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000294 AC: 430 AN: 1461298 Hom.: 1 Cov.: 35 AF XY: 0.000282 AC XY: 205 AN XY: 726942

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.000112 AC: 5 AN: 44702

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000368 AC: 409 AN: 1111610

Other (OTH) AF: 0.000199 AC: 12 AN: 60356

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74220

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15240

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.000221 AC: 15 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.0000828 AC: 10

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	1	not provided (7)
-	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	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 specified (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.93
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.45
MPC		0.45
ClinPred		0.24	T
GERP RS		6.2
Mutation Taster		=50/50

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: rs200732032; hg19: chr2-179457598; COSMIC: COSV60396823; COSMIC: COSV60396823;