rs55880440

Variant names:

• chr2-178529132-A-G
• rs55880440
• NM_001267550.2:c.106619T>C

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.106619T>C​(p.Ile35540Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,587,736 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 32)
  • Exomes 𝑓: 0.016 (238 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: 1.89
• Publications: 11 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050266385).
• BP6: Variant 2-178529132-A-G is Benign according to our data. Variant chr2-178529132-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47710.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 = 0.0113 (1723/152168) while in subpopulation NFE AF = 0.0169 (1151/67994). AF 95% confidence interval is 0.0161. There are 15 homozygotes in GnomAd4. There are 835 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.106619T>C	p.Ile35540Thr	missense	Exon 360 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.101696T>C	p.Ile33899Thr	missense	Exon 310 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.98915T>C	p.Ile32972Thr	missense	Exon 309 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.106619T>C	p.Ile35540Thr	missense	Exon 360 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.106463T>C	p.Ile35488Thr	missense	Exon 358 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.106343T>C	p.Ile35448Thr	missense	Exon 358 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1722 AN: 152050 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.0191

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.0122 AC: 2798 AN: 228956 AF XY: 0.0128

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.00505

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0000607

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0162 AC: 23258 AN: 1435568 Hom.: 238 Cov.: 32 AF XY: 0.0163 AC XY: 11584 AN XY: 711840

African (AFR) AF: 0.00257 AC: 82 AN: 31866

American (AMR) AF: 0.00541 AC: 215 AN: 39714

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 392 AN: 24984

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39440

South Asian (SAS) AF: 0.00732 AC: 597 AN: 81558

European-Finnish (FIN) AF: 0.0170 AC: 886 AN: 52224

Middle Eastern (MID) AF: 0.0183 AC: 103 AN: 5620

European-Non Finnish (NFE) AF: 0.0183 AC: 20158 AN: 1101092

Other (OTH) AF: 0.0139 AC: 823 AN: 59070

GnomAD4 genome AF: 0.0113 AC: 1723 AN: 152168 Hom.: 15 Cov.: 32 AF XY: 0.0112 AC XY: 835 AN XY: 74382

African (AFR) AF: 0.00378 AC: 157 AN: 41518

American (AMR) AF: 0.00667 AC: 102 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 66 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00727 AC: 35 AN: 4814

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10590

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0169 AC: 1151 AN: 67994

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0153 Hom.: 46

Bravo AF: 0.0107

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00414 AC: 15

ESP6500EA AF: 0.0178 AC: 145

ExAC AF: 0.0121 AC: 1456

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	13	not specified (13)
-	-	4	not provided (4)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.77
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.32
Sift	Benign	0.093	T
Polyphen		0.0	B
Vest4		0.17
MPC		0.11
ClinPred		0.017	T
GERP RS		1.6
Mutation Taster		=97/3	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: rs55880440; hg19: chr2-179393859; COSMIC: COSV99045593; COSMIC: COSV99045593;