rs72648998

Variant names:

• chr2-178710784-C-T
• rs72648998
• NM_001267550.2:c.28313G>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.28313G>A​(p.Arg9438Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 1,613,878 control chromosomes in the GnomAD database, including 2,698 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (181 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2517 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 2.81
• 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016161501).
• BP6: Variant 2-178710784-C-T is Benign according to our data. Variant chr2-178710784-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0577 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.28313G>A	p.Arg9438Gln	missense	Exon 98 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.27362G>A	p.Arg9121Gln	missense	Exon 96 of 313	NP_001243779.1
	TTN	NM_133378.4		c.24581G>A	p.Arg8194Gln	missense	Exon 95 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.28313G>A	p.Arg9438Gln	missense	Exon 98 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.28313G>A	p.Arg9438Gln	missense	Exon 98 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.28037G>A	p.Arg9346Gln	missense	Exon 96 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6211 AN: 152110 Hom.: 181 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0495

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0582

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0482 AC: 11999 AN: 249060 AF XY: 0.0473

Gnomad AFR exome AF: 0.00891

Gnomad AMR exome AF: 0.0947

Gnomad ASJ exome AF: 0.0538

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0194

Gnomad NFE exome AF: 0.0554

Gnomad OTH exome AF: 0.0482

GnomAD4 exome AF: 0.0556 AC: 81279 AN: 1461650 Hom.: 2517 Cov.: 32 AF XY: 0.0548 AC XY: 39876 AN XY: 727104

African (AFR) AF: 0.00908 AC: 304 AN: 33476

American (AMR) AF: 0.0912 AC: 4080 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0523 AC: 1368 AN: 26134

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39698

South Asian (SAS) AF: 0.0377 AC: 3254 AN: 86256

European-Finnish (FIN) AF: 0.0204 AC: 1092 AN: 53402

Middle Eastern (MID) AF: 0.0316 AC: 182 AN: 5764

European-Non Finnish (NFE) AF: 0.0610 AC: 67829 AN: 1111832

Other (OTH) AF: 0.0523 AC: 3160 AN: 60374

GnomAD4 genome AF: 0.0408 AC: 6212 AN: 152228 Hom.: 181 Cov.: 33 AF XY: 0.0390 AC XY: 2899 AN XY: 74412

African (AFR) AF: 0.0122 AC: 509 AN: 41552

American (AMR) AF: 0.0610 AC: 932 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 172 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4816

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0582 AC: 3957 AN: 68008

Other (OTH) AF: 0.0331 AC: 70 AN: 2112

Alfa AF: 0.0522 Hom.: 870

Bravo AF: 0.0451

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0625 AC: 241

ESP6500AA AF: 0.0141 AC: 56

ESP6500EA AF: 0.0570 AC: 476

ExAC AF: 0.0450 AC: 5446

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0555

EpiControl AF: 0.0549

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	13	not specified (13)
-	-	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	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	0.044
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.76	T
PhyloP100		2.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.32	T
Polyphen		0.17	B
Vest4		0.15
MPC		0.10
ClinPred		0.0076	T
GERP RS		5.3
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72648998; hg19: chr2-179575511; COSMIC: COSV60192997;