rs72629779

Variant names:

• chr2-178536288-G-A
• rs72629779
• NM_001267550.2:c.100459C>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.100459C>T​(p.Pro33487Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,642 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 8.13
• Publications: 4 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=0.0054626763).
• BP6: Variant 2-178536288-G-A is Benign according to our data. Variant chr2-178536288-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1709/152262) while in subpopulation AFR AF = 0.0386 (1603/41540). AF 95% confidence interval is 0.037. There are 34 homozygotes in GnomAd4. There are 788 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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.100459C>T	p.Pro33487Ser	missense	Exon 357 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.95536C>T	p.Pro31846Ser	missense	Exon 307 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.92755C>T	p.Pro30919Ser	missense	Exon 306 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.100459C>T	p.Pro33487Ser	missense	Exon 357 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.100303C>T	p.Pro33435Ser	missense	Exon 355 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.100183C>T	p.Pro33395Ser	missense	Exon 355 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1705 AN: 152144 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00285 AC: 707 AN: 248470 AF XY: 0.00224

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000889

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00114 AC: 1669 AN: 1461380 Hom.: 30 Cov.: 33 AF XY: 0.000963 AC XY: 700 AN XY: 726948

African (AFR) AF: 0.0402 AC: 1344 AN: 33466

American (AMR) AF: 0.00246 AC: 110 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111732

Other (OTH) AF: 0.00280 AC: 169 AN: 60358

GnomAD4 genome AF: 0.0112 AC: 1709 AN: 152262 Hom.: 34 Cov.: 33 AF XY: 0.0106 AC XY: 788 AN XY: 74452

African (AFR) AF: 0.0386 AC: 1603 AN: 41540

American (AMR) AF: 0.00490 AC: 75 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00434 Hom.: 21

Bravo AF: 0.0127

ESP6500AA AF: 0.0338 AC: 127

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00353 AC: 427

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.97
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		8.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.35
Sift	Benign	0.075	T
Polyphen		1.0	D
Vest4		0.37
MVP		0.35
MPC		0.46
ClinPred		0.044	T
GERP RS		5.8
Mutation Taster		=93/7	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: rs72629779; hg19: chr2-179401015; COSMIC: COSV99045618; COSMIC: COSV99045618;