rs9808377

Variant names:

• chr2-178556967-A-G
• rs9808377
• NM_001267550.2:c.88187T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178556967-A-G
• chr2-178556967-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.88187T>C​(p.Ile29396Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,436 control chromosomes in the GnomAD database, including 73,989 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I29396L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (11804 hom., cov: 32)
  • Exomes 𝑓: 0.27 (62185 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 0.721
• Publications: 47 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8822432E-6).
• BP6: Variant 2-178556967-A-G is Benign according to our data. Variant chr2-178556967-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

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.88187T>C	p.Ile29396Thr	missense	Exon 330 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.83264T>C	p.Ile27755Thr	missense	Exon 280 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.80483T>C	p.Ile26828Thr	missense	Exon 279 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.88187T>C	p.Ile29396Thr	missense	Exon 330 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.88031T>C	p.Ile29344Thr	missense	Exon 328 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.87911T>C	p.Ile29304Thr	missense	Exon 328 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54733 AN: 151894 Hom.: 11755 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.351 AC: 87123 AN: 248424 AF XY: 0.348

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.424

Gnomad ASJ exome AF: 0.280

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.266 AC: 389351 AN: 1461424 Hom.: 62185 Cov.: 36 AF XY: 0.272 AC XY: 197456 AN XY: 726996

African (AFR) AF: 0.555 AC: 18577 AN: 33476

American (AMR) AF: 0.423 AC: 18919 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 7289 AN: 26130

East Asian (EAS) AF: 0.692 AC: 27432 AN: 39618

South Asian (SAS) AF: 0.503 AC: 43395 AN: 86246

European-Finnish (FIN) AF: 0.277 AC: 14772 AN: 53386

Middle Eastern (MID) AF: 0.306 AC: 1764 AN: 5766

European-Non Finnish (NFE) AF: 0.215 AC: 239024 AN: 1111738

Other (OTH) AF: 0.301 AC: 18179 AN: 60360

GnomAD4 genome AF: 0.361 AC: 54843 AN: 152012 Hom.: 11804 Cov.: 32 AF XY: 0.371 AC XY: 27533 AN XY: 74308

African (AFR) AF: 0.542 AC: 22469 AN: 41426

American (AMR) AF: 0.381 AC: 5829 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 980 AN: 3470

East Asian (EAS) AF: 0.699 AC: 3594 AN: 5140

South Asian (SAS) AF: 0.514 AC: 2475 AN: 4818

European-Finnish (FIN) AF: 0.285 AC: 3015 AN: 10584

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.223 AC: 15181 AN: 67980

Other (OTH) AF: 0.334 AC: 705 AN: 2112

Alfa AF: 0.279 Hom.: 24479

Bravo AF: 0.375

TwinsUK AF: 0.211 AC: 784

ALSPAC AF: 0.214 AC: 825

ESP6500AA AF: 0.524 AC: 2066

ESP6500EA AF: 0.221 AC: 1831

ExAC AF: 0.350 AC: 42317

Asia WGS AF: 0.619 AC: 2150 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.227

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.7
DANN	Benign	0.54
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-2.6	N
PhyloP100		0.72
PrimateAI	Benign	0.30	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.11
ClinPred		0.0059	T
GERP RS		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs9808377; hg19: chr2-179421694; COSMIC: COSV60092398;