rs2042995

Variant names:

• chr2-178693639-T-C
• rs2042995
• NM_001267550.2:c.31564A>G

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.31564A>G​(p.Ile10522Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,596,826 control chromosomes in the GnomAD database, including 69,862 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. I10522I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (11636 hom., cov: 32)
  • Exomes 𝑓: 0.27 (58226 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 1.46
• Publications: 49 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=3.0493736E-4).
• BP6: Variant 2-178693639-T-C is Benign according to our data. Variant chr2-178693639-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 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.31564A>G	p.Ile10522Val	missense	Exon 119 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.30613A>G	p.Ile10205Val	missense	Exon 117 of 313	NP_001243779.1
	TTN	NM_133378.4		c.27832A>G	p.Ile9278Val	missense	Exon 116 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.31564A>G	p.Ile10522Val	missense	Exon 119 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.31564A>G	p.Ile10522Val	missense	Exon 119 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.31288A>G	p.Ile10430Val	missense	Exon 117 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54609 AN: 151908 Hom.: 11586 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.337 AC: 82484 AN: 245066 AF XY: 0.332

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.574

Gnomad FIN exome AF: 0.252

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.265 AC: 382959 AN: 1444798 Hom.: 58226 Cov.: 31 AF XY: 0.269 AC XY: 192594 AN XY: 716090

African (AFR) AF: 0.567 AC: 18756 AN: 33106

American (AMR) AF: 0.429 AC: 18861 AN: 43960

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6892 AN: 25908

East Asian (EAS) AF: 0.559 AC: 21958 AN: 39304

South Asian (SAS) AF: 0.469 AC: 39231 AN: 83580

European-Finnish (FIN) AF: 0.252 AC: 13363 AN: 53096

Middle Eastern (MID) AF: 0.305 AC: 1745 AN: 5726

European-Non Finnish (NFE) AF: 0.222 AC: 244558 AN: 1100434

Other (OTH) AF: 0.295 AC: 17595 AN: 59684

GnomAD4 genome AF: 0.360 AC: 54721 AN: 152028 Hom.: 11636 Cov.: 32 AF XY: 0.367 AC XY: 27299 AN XY: 74326

African (AFR) AF: 0.553 AC: 22931 AN: 41444

American (AMR) AF: 0.391 AC: 5959 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 927 AN: 3470

East Asian (EAS) AF: 0.572 AC: 2967 AN: 5188

South Asian (SAS) AF: 0.482 AC: 2323 AN: 4816

European-Finnish (FIN) AF: 0.260 AC: 2755 AN: 10576

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15563 AN: 67966

Other (OTH) AF: 0.335 AC: 705 AN: 2106

Alfa AF: 0.271 Hom.: 27680

Bravo AF: 0.377

TwinsUK AF: 0.218 AC: 809

ALSPAC AF: 0.222 AC: 854

ESP6500AA AF: 0.559 AC: 2003

ESP6500EA AF: 0.229 AC: 1858

ExAC AF: 0.338 AC: 40747

Asia WGS AF: 0.543 AC: 1889 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	0.059
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0020
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.00030	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Vest4		0.025
ClinPred		0.0060	T
GERP RS		5.8
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2042995; hg19: chr2-179558366; COSMIC: COSV60092594;