rs34070843

Variant names:

• chr2-178740998-T-C
• rs34070843
• NM_001267550.2:c.12235A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.12235A>G​(p.Ile4079Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,613,934 control chromosomes in the GnomAD database, including 430 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 32)
  • Exomes 𝑓: 0.020 (394 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.332
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003384471).
• BP6: Variant 2-178740998-T-C is Benign according to our data. Variant chr2-178740998-T-C is described in ClinVar as Benign. ClinVar VariationId is 47823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0144 (2198/152316) while in subpopulation SAS AF = 0.0427 (206/4826). AF 95% confidence interval is 0.0379. There are 36 homozygotes in GnomAd4. There are 1074 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AD,AR gene

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.12235A>G	p.Ile4079Val	missense	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.11284A>G	p.Ile3762Val	missense	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.11722A>G	p.Ile3908Val	missense	Exon 46 of 192	NP_597681.4	A0A0A0MRA3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.12235A>G	p.Ile4079Val	missense	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.12235A>G	p.Ile4079Val	missense	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11959A>G	p.Ile3987Val	missense	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2201 AN: 152198 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0176 AC: 4374 AN: 248276 AF XY: 0.0194

Gnomad AFR exome AF: 0.00368

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00172

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0204 AC: 29879 AN: 1461618 Hom.: 394 Cov.: 32 AF XY: 0.0211 AC XY: 15314 AN XY: 727092

African (AFR) AF: 0.00317 AC: 106 AN: 33476

American (AMR) AF: 0.0179 AC: 801 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 392 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.0422 AC: 3639 AN: 86258

European-Finnish (FIN) AF: 0.00212 AC: 113 AN: 53400

Middle Eastern (MID) AF: 0.0420 AC: 242 AN: 5764

European-Non Finnish (NFE) AF: 0.0210 AC: 23323 AN: 1111810

Other (OTH) AF: 0.0209 AC: 1259 AN: 60368

GnomAD4 genome AF: 0.0144 AC: 2198 AN: 152316 Hom.: 36 Cov.: 32 AF XY: 0.0144 AC XY: 1074 AN XY: 74456

African (AFR) AF: 0.00433 AC: 180 AN: 41572

American (AMR) AF: 0.0250 AC: 383 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 32 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0427 AC: 206 AN: 4826

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10612

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1304 AN: 68034

Other (OTH) AF: 0.0236 AC: 50 AN: 2116

Alfa AF: 0.0179 Hom.: 94

Bravo AF: 0.0147

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00538 AC: 20

ESP6500EA AF: 0.0185 AC: 152

ExAC AF: 0.0179 AC: 2157

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0254

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	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	Cardiovascular phenotype (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	0.071
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.6
DANN	Benign	0.50
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.33
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.073
Sift	Benign	0.67	T
Vest4		0.025
MPC		0.070
ClinPred		0.00065	T
GERP RS		-1.7
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: rs34070843; hg19: chr2-179605725;