rs34819099

Variant names:

• chr2-178764191-C-T
• rs34819099
• NM_001267550.2:c.10100G>A
• TTN p.Arg3367Gln

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.10100G>A​(p.Arg3367Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,078 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. R3367W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (10 hom., cov: 33)
  • Exomes 𝑓: 0.015 (187 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.765
• Publications: 19 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=0.0077604353).
• BP6: Variant 2-178764191-C-T is Benign according to our data. Variant chr2-178764191-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00961 (1463/152276) while in subpopulation NFE AF = 0.0157 (1069/68028). AF 95% confidence interval is 0.0149. There are 10 homozygotes in GnomAd4. There are 680 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.10100G>A	p.Arg3367Gln	missense	Exon 43 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10100G>A	p.Arg3367Gln	missense	Exon 43 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10100G>A	p.Arg3367Gln	missense	Exon 43 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.10100G>A	p.Arg3367Gln	missense	Exon 43 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.10100G>A	p.Arg3367Gln	missense	Exon 43 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.9824G>A	p.Arg3275Gln	missense	Exon 41 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00962 AC: 1463 AN: 152158 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.0102 AC: 2554 AN: 251330 AF XY: 0.0110

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0153 AC: 22341 AN: 1461802 Hom.: 187 Cov.: 32 AF XY: 0.0152 AC XY: 11036 AN XY: 727206

African (AFR) AF: 0.00260 AC: 87 AN: 33478

American (AMR) AF: 0.00557 AC: 249 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0223 AC: 584 AN: 26134

East Asian (EAS) AF: 0.00128 AC: 51 AN: 39694

South Asian (SAS) AF: 0.00716 AC: 618 AN: 86256

European-Finnish (FIN) AF: 0.00264 AC: 141 AN: 53416

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0177 AC: 19684 AN: 1111938

Other (OTH) AF: 0.0149 AC: 898 AN: 60394

GnomAD4 genome AF: 0.00961 AC: 1463 AN: 152276 Hom.: 10 Cov.: 33 AF XY: 0.00913 AC XY: 680 AN XY: 74452

African (AFR) AF: 0.00301 AC: 125 AN: 41558

American (AMR) AF: 0.00602 AC: 92 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0157 AC: 1069 AN: 68028

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.0143 Hom.: 69

Bravo AF: 0.0104

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0164

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	4	not provided (4)
-	-	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	0.088
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.77
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.051
Sift	Benign	0.30	T
Sift4G	Benign	0.20	T
Mutation Taster		=92/8	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34819099;

hg19: chr2-179628918;