rs727504672

Variant names:

• chr2-178550106-C-T
• rs727504672
• NM_001267550.2:c.91732G>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.91732G>A​(p.Val30578Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:5
• Conservation: PhyloP100: 5.97
• 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]

ENSG00000270277 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22247612).
• BP6: Variant 2-178550106-C-T is Benign according to our data. Variant chr2-178550106-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179154.

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.91732G>A	p.Val30578Ile	missense	Exon 337 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.86809G>A	p.Val28937Ile	missense	Exon 287 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.84028G>A	p.Val28010Ile	missense	Exon 286 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.91732G>A	p.Val30578Ile	missense	Exon 337 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.91576G>A	p.Val30526Ile	missense	Exon 335 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.91456G>A	p.Val30486Ile	missense	Exon 335 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000803 AC: 20 AN: 248930 AF XY: 0.0000741

Gnomad AFR exome AF: 0.0000646

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: 0.000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461552 Hom.: 0 Cov.: 32 AF XY: 0.0000811 AC XY: 59 AN XY: 727056

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1111768

Other (OTH) AF: 0.000166 AC: 10 AN: 60370

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74448

African (AFR) AF: 0.0000722 AC: 3 AN: 41552

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

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

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000745 AC: 9

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (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	0.073
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.97
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.45	N
PhyloP100		6.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.24
Sift	Benign	0.27	T
Polyphen		0.96	D
Vest4		0.26
MVP		0.55
MPC		0.13
ClinPred		0.13	T
GERP RS		5.7
Mutation Taster		=90/10	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: rs727504672; hg19: chr2-179414833; COSMIC: COSV60165346; COSMIC: COSV60165346;