rs2244492

Variant names:

• chr2-178689578-C-T
• rs2244492
• NM_001267550.2:c.31864G>A

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.31864G>A​(p.Gly10622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,603,082 control chromosomes in the GnomAD database, including 122,135 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G10622E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.44 (15809 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106326 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.72
• Publications: 37 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]

LOC124907912 (HGNC:):

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=2.2068143E-5).
• BP6: Variant 2-178689578-C-T is Benign according to our data. Variant chr2-178689578-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 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.31864G>A	p.Gly10622Arg	missense	Exon 123 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.30913G>A	p.Gly10305Arg	missense	Exon 121 of 313	NP_001243779.1
	TTN	NM_133378.4		c.28132G>A	p.Gly9378Arg	missense	Exon 120 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.31864G>A	p.Gly10622Arg	missense	Exon 123 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.31864G>A	p.Gly10622Arg	missense	Exon 123 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.31588G>A	p.Gly10530Arg	missense	Exon 121 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66544 AN: 151906 Hom.: 15767 Cov.: 32

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.380 AC: 89586 AN: 235902 AF XY: 0.377

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.377 AC: 546651 AN: 1451056 Hom.: 106326 Cov.: 34 AF XY: 0.377 AC XY: 271718 AN XY: 721110

African (AFR) AF: 0.618 AC: 20560 AN: 33244

American (AMR) AF: 0.366 AC: 15766 AN: 43084

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 7135 AN: 25908

East Asian (EAS) AF: 0.149 AC: 5920 AN: 39614

South Asian (SAS) AF: 0.450 AC: 38035 AN: 84548

European-Finnish (FIN) AF: 0.497 AC: 26305 AN: 52916

Middle Eastern (MID) AF: 0.301 AC: 1727 AN: 5742

European-Non Finnish (NFE) AF: 0.370 AC: 408753 AN: 1106044

Other (OTH) AF: 0.374 AC: 22450 AN: 59956

GnomAD4 genome AF: 0.438 AC: 66650 AN: 152026 Hom.: 15809 Cov.: 32 AF XY: 0.441 AC XY: 32745 AN XY: 74286

African (AFR) AF: 0.602 AC: 24957 AN: 41470

American (AMR) AF: 0.391 AC: 5963 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 961 AN: 3470

East Asian (EAS) AF: 0.170 AC: 881 AN: 5172

South Asian (SAS) AF: 0.458 AC: 2208 AN: 4822

European-Finnish (FIN) AF: 0.505 AC: 5332 AN: 10566

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25170 AN: 67948

Other (OTH) AF: 0.379 AC: 798 AN: 2106

Alfa AF: 0.376 Hom.: 49558

Bravo AF: 0.429

TwinsUK AF: 0.369 AC: 1369

ALSPAC AF: 0.381 AC: 1469

ESP6500AA AF: 0.595 AC: 2207

ESP6500EA AF: 0.360 AC: 2955

ExAC AF: 0.378 AC: 45629

Asia WGS AF: 0.337 AC: 1169 AN: 3476

ClinVar

ClinVar submissions as Germline

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	0.063
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.000022	T
MetaSVM	Benign	-0.95	T
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.094
Sift	Benign	0.80	T
Vest4		0.072
MutPred		0.36		Gain of MoRF binding (P = 0.0075)
ClinPred		0.012	T
GERP RS		5.3
Mutation Taster		=91/9	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: rs2244492; hg19: chr2-179554305; COSMIC: COSV59946355;