2-178549435-T-C

Variant names:

• chr2-178549435-T-C
• rs16866391
• NM_001267550.2:c.92191A>G

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.92191A>G​(p.Ile30731Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,610,898 control chromosomes in the GnomAD database, including 1,504 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. I30731L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (155 hom., cov: 33)
  • Exomes 𝑓: 0.011 (1349 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.441
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010635853).
• BP6: Variant 2-178549435-T-C is Benign according to our data. Variant chr2-178549435-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 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.92191A>G	p.Ile30731Val	missense	Exon 339 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.87268A>G	p.Ile29090Val	missense	Exon 289 of 313	NP_001243779.1
	TTN	NM_133378.4		c.84487A>G	p.Ile28163Val	missense	Exon 288 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.92191A>G	p.Ile30731Val	missense	Exon 339 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.92035A>G	p.Ile30679Val	missense	Exon 337 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.91915A>G	p.Ile30639Val	missense	Exon 337 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2365 AN: 152186 Hom.: 152 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0715

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0383 AC: 9490 AN: 247460 AF XY: 0.0297

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.000800

Gnomad EAS exome AF: 0.0655

Gnomad FIN exome AF: 0.00210

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0105 AC: 15318 AN: 1458594 Hom.: 1349 Cov.: 35 AF XY: 0.00946 AC XY: 6857 AN XY: 725010

African (AFR) AF: 0.00240 AC: 80 AN: 33322

American (AMR) AF: 0.210 AC: 9359 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26082

East Asian (EAS) AF: 0.0865 AC: 3430 AN: 39636

South Asian (SAS) AF: 0.00493 AC: 425 AN: 86206

European-Finnish (FIN) AF: 0.00221 AC: 118 AN: 53308

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5750

European-Non Finnish (NFE) AF: 0.00114 AC: 1267 AN: 1109492

Other (OTH) AF: 0.00996 AC: 600 AN: 60228

GnomAD4 genome AF: 0.0156 AC: 2377 AN: 152304 Hom.: 155 Cov.: 33 AF XY: 0.0166 AC XY: 1234 AN XY: 74468

African (AFR) AF: 0.00293 AC: 122 AN: 41580

American (AMR) AF: 0.111 AC: 1693 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.0716 AC: 371 AN: 5178

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4824

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68024

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00857 Hom.: 184

Bravo AF: 0.0279

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00285 AC: 11

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.0311 AC: 3758

Asia WGS AF: 0.0370 AC: 127 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00125

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	3	not provided (3)
-	-	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	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.1
DANN	Benign	0.62
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.18	N
PhyloP100		0.44
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.062
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.070
ClinPred		0.00065	T
GERP RS		-0.22
Mutation Taster		=99/1	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: rs16866391; hg19: chr2-179414162; COSMIC: COSV59948225;