2-178732710-T-C

Variant names:

• chr2-178732710-T-C
• rs760722200
• NM_001267550.2:c.16351A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000589042.5(TTN):​c.16351A>G​(p.Ser5451Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,588,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. S5451C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.98
• Publications: 1 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=0.19758666).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.16351A>G	p.Ser5451Gly	missense	Exon 56 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.15400A>G	p.Ser5134Gly	missense	Exon 54 of 313	NP_001243779.1
	TTN	NM_133378.4		c.12619A>G	p.Ser4207Gly	missense	Exon 53 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.16351A>G	p.Ser5451Gly	missense	Exon 56 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.16351A>G	p.Ser5451Gly	missense	Exon 56 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.16075A>G	p.Ser5359Gly	missense	Exon 54 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152116 Hom.: 0 Cov.: 33

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000177 AC: 4 AN: 226524 AF XY: 0.0000245

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000384

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000271 AC: 39 AN: 1436628 Hom.: 0 Cov.: 36 AF XY: 0.0000168 AC XY: 12 AN XY: 712324

African (AFR) AF: 0.00 AC: 0 AN: 32356

American (AMR) AF: 0.00 AC: 0 AN: 40966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24800

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.00 AC: 0 AN: 82056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52442

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5608

European-Non Finnish (NFE) AF: 0.0000345 AC: 38 AN: 1099966

Other (OTH) AF: 0.00 AC: 0 AN: 59174

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152116 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	Cardiomyopathy (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.93
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.48	T
PhyloP100		2.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.35	T
Polyphen		0.18	B
Vest4		0.31
MutPred		0.39		Loss of phosphorylation at S5134 (P = 0.0531)
MVP		0.23
MPC		0.090
ClinPred		0.074	T
GERP RS		4.8
Mutation Taster		=63/37	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: rs760722200; hg19: chr2-179597437;