chr2-178577205-G-A

Variant names:

• chr2-178577205-G-A
• rs55980498
• NM_001267550.2:c.69130C>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.69130C>T​(p.Pro23044Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,612,852 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts 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. P23044P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (28 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:17
• Conservation: PhyloP100: 8.08
• Publications: 20 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]

ENSG00000271011 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009799123).
• BP6: Variant 2-178577205-G-A is Benign according to our data. Variant chr2-178577205-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47265.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 = 0.00361 (549/151934) while in subpopulation NFE AF = 0.00567 (385/67950). AF 95% confidence interval is 0.0052. There are 1 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 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.69130C>T	p.Pro23044Ser	missense	Exon 324 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.64207C>T	p.Pro21403Ser	missense	Exon 274 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.61426C>T	p.Pro20476Ser	missense	Exon 273 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.69130C>T	p.Pro23044Ser	missense	Exon 324 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.68974C>T	p.Pro22992Ser	missense	Exon 322 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.68854C>T	p.Pro22952Ser	missense	Exon 322 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 549 AN: 151814 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00557

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00567

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00362 AC: 896 AN: 247582 AF XY: 0.00364

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00549

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00531 AC: 7758 AN: 1460918 Hom.: 28 Cov.: 35 AF XY: 0.00521 AC XY: 3783 AN XY: 726750

African (AFR) AF: 0.00111 AC: 37 AN: 33446

American (AMR) AF: 0.00231 AC: 103 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26116

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39486

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86234

European-Finnish (FIN) AF: 0.00596 AC: 318 AN: 53350

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5758

European-Non Finnish (NFE) AF: 0.00615 AC: 6840 AN: 1111520

Other (OTH) AF: 0.00467 AC: 282 AN: 60324

GnomAD4 genome AF: 0.00361 AC: 549 AN: 151934 Hom.: 1 Cov.: 32 AF XY: 0.00372 AC XY: 276 AN XY: 74218

African (AFR) AF: 0.00130 AC: 54 AN: 41462

American (AMR) AF: 0.00190 AC: 29 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00230 AC: 11 AN: 4790

European-Finnish (FIN) AF: 0.00557 AC: 59 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00567 AC: 385 AN: 67950

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00469 Hom.: 5

Bravo AF: 0.00344

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00179 AC: 7

ESP6500EA AF: 0.00519 AC: 43

ExAC AF: 0.00339 AC: 410

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00493

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Atrial fibrillation;C0007194:Hypertrophic cardiomyopathy;C0018802:Congestive heart failure;C1142166:Brugada syndrome (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
1	-	-	Tip-toe gait (1)
-	-	1	TTN-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.92
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.021	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.021	D
Polyphen		0.96	D
Vest4		0.41
MVP		0.56
MPC		0.24
ClinPred		0.073	T
GERP RS		5.6
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs55980498; hg19: chr2-179441932;