rs72650006

Variant names:

• chr2-178704660-T-A
• rs72650006
• NM_001267550.2:c.29812A>T

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.29812A>T​(p.Thr9938Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,612,220 control chromosomes in the GnomAD database, including 442 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T9938T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (40 hom., cov: 33)
  • Exomes 𝑓: 0.022 (402 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 6.24
• Publications: 9 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=0.003761977).
• BP6: Variant 2-178704660-T-A is Benign according to our data. Variant chr2-178704660-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0191 (2905/152314) while in subpopulation AMR AF = 0.0282 (431/15302). AF 95% confidence interval is 0.026. There are 40 homozygotes in GnomAd4. There are 1437 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.29812A>T	p.Thr9938Ser	missense	Exon 105 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.28861A>T	p.Thr9621Ser	missense	Exon 103 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26080A>T	p.Thr8694Ser	missense	Exon 102 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.29812A>T	p.Thr9938Ser	missense	Exon 105 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.29812A>T	p.Thr9938Ser	missense	Exon 105 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.29536A>T	p.Thr9846Ser	missense	Exon 103 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2907 AN: 152196 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0193 AC: 4733 AN: 245040 AF XY: 0.0194

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.0254

Gnomad OTH exome AF: 0.0226

GnomAD4 exome AF: 0.0222 AC: 32363 AN: 1459906 Hom.: 402 Cov.: 32 AF XY: 0.0222 AC XY: 16101 AN XY: 726070

African (AFR) AF: 0.00376 AC: 126 AN: 33472

American (AMR) AF: 0.0162 AC: 721 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 410 AN: 26084

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39688

South Asian (SAS) AF: 0.0157 AC: 1353 AN: 86074

European-Finnish (FIN) AF: 0.0272 AC: 1448 AN: 53156

Middle Eastern (MID) AF: 0.0226 AC: 130 AN: 5762

European-Non Finnish (NFE) AF: 0.0243 AC: 26955 AN: 1110888

Other (OTH) AF: 0.0202 AC: 1216 AN: 60284

GnomAD4 genome AF: 0.0191 AC: 2905 AN: 152314 Hom.: 40 Cov.: 33 AF XY: 0.0193 AC XY: 1437 AN XY: 74480

African (AFR) AF: 0.00507 AC: 211 AN: 41584

American (AMR) AF: 0.0282 AC: 431 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4822

European-Finnish (FIN) AF: 0.0250 AC: 266 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0266 AC: 1812 AN: 68016

Other (OTH) AF: 0.0223 AC: 47 AN: 2110

Alfa AF: 0.0218 Hom.: 14

Bravo AF: 0.0179

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00683 AC: 25

ESP6500EA AF: 0.0266 AC: 217

ExAC AF: 0.0190 AC: 2300

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.90
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
PhyloP100		6.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.10
Sift	Benign	0.49	T
Polyphen		0.15	B
Vest4		0.095
MutPred		0.47		Gain of disorder (P = 0.0412)
MPC		0.10
ClinPred		0.013	T
GERP RS		5.8
Mutation Taster		=49/51	polymorphism (auto)

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: rs72650006; hg19: chr2-179569387;