chr2-178550265-T-C

Variant names:

• chr2-178550265-T-C
• rs72648244
• NM_001267550.2:c.91573A>G

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.91573A>G​(p.Ile30525Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,606,414 control chromosomes in the GnomAD database, including 64 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 0.0060 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (58 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: 1.82
• Publications: 14 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]

ENSG00000270277 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004075378).
• BP6: Variant 2-178550265-T-C is Benign according to our data. Variant chr2-178550265-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47511.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 = 0.00599 (912/152268) while in subpopulation NFE AF = 0.00983 (669/68032). AF 95% confidence interval is 0.00922. There are 6 homozygotes in GnomAd4. There are 418 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.91573A>G	p.Ile30525Val	missense	Exon 337 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.86650A>G	p.Ile28884Val	missense	Exon 287 of 313	NP_001243779.1
	TTN	NM_133378.4		c.83869A>G	p.Ile27957Val	missense	Exon 286 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.91573A>G	p.Ile30525Val	missense	Exon 337 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.91417A>G	p.Ile30473Val	missense	Exon 335 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.91297A>G	p.Ile30433Val	missense	Exon 335 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 912 AN: 152150 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00983

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00622 AC: 1521 AN: 244436 AF XY: 0.00634

Gnomad AFR exome AF: 0.00223

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00440

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00906

Gnomad NFE exome AF: 0.00987

Gnomad OTH exome AF: 0.00679

GnomAD4 exome AF: 0.00804 AC: 11687 AN: 1454146 Hom.: 58 Cov.: 32 AF XY: 0.00786 AC XY: 5683 AN XY: 722642

African (AFR) AF: 0.00197 AC: 65 AN: 33042

American (AMR) AF: 0.00202 AC: 89 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 114 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00176 AC: 150 AN: 85464

European-Finnish (FIN) AF: 0.00919 AC: 484 AN: 52652

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5720

European-Non Finnish (NFE) AF: 0.00930 AC: 10301 AN: 1107796

Other (OTH) AF: 0.00798 AC: 479 AN: 60016

GnomAD4 genome AF: 0.00599 AC: 912 AN: 152268 Hom.: 6 Cov.: 33 AF XY: 0.00562 AC XY: 418 AN XY: 74440

African (AFR) AF: 0.00180 AC: 75 AN: 41562

American (AMR) AF: 0.00268 AC: 41 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00820 AC: 87 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00983 AC: 669 AN: 68032

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00759 Hom.: 15

Bravo AF: 0.00532

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00277 AC: 10

ESP6500EA AF: 0.00969 AC: 79

ExAC AF: 0.00679 AC: 820

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00852

EpiControl AF: 0.00851

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	-	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)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.84
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		1.8
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.065
Sift	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.35
MPC		0.070
ClinPred		0.0066	T
GERP RS		4.6
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs72648244; hg19: chr2-179414992; COSMIC: COSV99045614; COSMIC: COSV99045614;