rs886055288

Variant names:

• chr2-178696131-A-G
• rs886055288
• NM_001267550.2:c.30941T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178696131-A-G
• chr2-178696131-A-T

Variant summary

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

The NM_001267550.2(TTN):​c.30941T>C​(p.Ile10314Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,552,324 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I10314I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 2.79
• Publications: 0 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18574753).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.30941T>C	p.Ile10314Thr	missense	Exon 114 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.29990T>C	p.Ile9997Thr	missense	Exon 112 of 313	NP_001243779.1
	TTN	NM_133378.4		c.27209T>C	p.Ile9070Thr	missense	Exon 111 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.30941T>C	p.Ile10314Thr	missense	Exon 114 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30941T>C	p.Ile10314Thr	missense	Exon 114 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30665T>C	p.Ile10222Thr	missense	Exon 112 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000250 AC: 4 AN: 160092 AF XY: 0.0000118

Gnomad AFR exome AF: 0.000119

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: 0.0000319

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000236 AC: 33 AN: 1400254 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 19 AN XY: 690736

African (AFR) AF: 0.0000315 AC: 1 AN: 31702

American (AMR) AF: 0.00 AC: 0 AN: 35742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00 AC: 0 AN: 35952

South Asian (SAS) AF: 0.0000504 AC: 4 AN: 79380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000241 AC: 26 AN: 1079166

Other (OTH) AF: 0.0000345 AC: 2 AN: 58038

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74296

African (AFR) AF: 0.0000965 AC: 4 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (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	-	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	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.00015
Eigen_PC	Benign	0.0072
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.55	T
PhyloP100		2.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Polyphen		0.28	B
Vest4		0.34
MutPred		0.35		Gain of phosphorylation at I9997 (P = 0.0106)
MVP		0.70
MPC		0.12
ClinPred		0.093	T
GERP RS		5.8
Mutation Taster		=80/20	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: rs886055288; hg19: chr2-179560858;