rs2303838

Variant names:

• chr2-178580212-C-T
• rs2303838
• NM_001267550.2:c.67075G>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.67075G>A​(p.Val22359Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,612,158 control chromosomes in the GnomAD database, including 39,664 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5385 hom., cov: 33)
  • Exomes 𝑓: 0.20 (34279 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -0.0140
• Publications: 34 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]

ENSG00000270574 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=6.291586E-6).
• BP6: Variant 2-178580212-C-T is Benign according to our data. Variant chr2-178580212-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) 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.67075G>A	p.Val22359Ile	missense	Exon 318 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.62152G>A	p.Val20718Ile	missense	Exon 268 of 313	NP_001243779.1
	TTN	NM_133378.4		c.59371G>A	p.Val19791Ile	missense	Exon 267 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.67075G>A	p.Val22359Ile	missense	Exon 318 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.66919G>A	p.Val22307Ile	missense	Exon 316 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.66799G>A	p.Val22267Ile	missense	Exon 316 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37201 AN: 151832 Hom.: 5377 Cov.: 33

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.240 AC: 59384 AN: 247486 AF XY: 0.242

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.198 AC: 288796 AN: 1460208 Hom.: 34279 Cov.: 36 AF XY: 0.201 AC XY: 146013 AN XY: 726354

African (AFR) AF: 0.339 AC: 11303 AN: 33390

American (AMR) AF: 0.196 AC: 8763 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 6163 AN: 26104

East Asian (EAS) AF: 0.614 AC: 24270 AN: 39520

South Asian (SAS) AF: 0.324 AC: 27865 AN: 86086

European-Finnish (FIN) AF: 0.170 AC: 9065 AN: 53342

Middle Eastern (MID) AF: 0.252 AC: 1452 AN: 5752

European-Non Finnish (NFE) AF: 0.168 AC: 186439 AN: 1111078

Other (OTH) AF: 0.224 AC: 13476 AN: 60284

GnomAD4 genome AF: 0.245 AC: 37237 AN: 151950 Hom.: 5385 Cov.: 33 AF XY: 0.249 AC XY: 18462 AN XY: 74272

African (AFR) AF: 0.335 AC: 13878 AN: 41438

American (AMR) AF: 0.200 AC: 3047 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 821 AN: 3468

East Asian (EAS) AF: 0.613 AC: 3143 AN: 5124

South Asian (SAS) AF: 0.327 AC: 1571 AN: 4810

European-Finnish (FIN) AF: 0.182 AC: 1925 AN: 10582

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11837 AN: 67952

Other (OTH) AF: 0.242 AC: 511 AN: 2112

Alfa AF: 0.203 Hom.: 16345

Bravo AF: 0.252

TwinsUK AF: 0.163 AC: 604

ALSPAC AF: 0.168 AC: 648

ESP6500AA AF: 0.329 AC: 1207

ESP6500EA AF: 0.177 AC: 1445

ExAC AF: 0.242 AC: 29206

Asia WGS AF: 0.455 AC: 1582 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.182

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	0.077
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.89
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0000063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.014
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.029
Sift	Benign	0.073	T
Polyphen		0.0030	B
Vest4		0.035
MPC		0.070
ClinPred		0.0013	T
GERP RS		2.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2303838; hg19: chr2-179444939; COSMIC: COSV60287542; COSMIC: COSV60287542;