rs190149868

Variant names:

• chr2-178575371-C-A
• rs190149868
• NM_001267550.2:c.70761G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178575371-C-A
• chr2-178575371-C-G
• chr2-178575371-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001267550.2(TTN):​c.70761G>T​(p.Gly23587Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000995 in 1,613,616 control chromosomes in the GnomAD database, including 22 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. G23587G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (17 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.40
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-178575371-C-A is Benign according to our data. Variant chr2-178575371-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 467436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.70761G>T	p.Gly23587Gly	synonymous	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.65838G>T	p.Gly21946Gly	synonymous	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.63057G>T	p.Gly21019Gly	synonymous	Exon 275 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.70761G>T	p.Gly23587Gly	synonymous	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.70605G>T	p.Gly23535Gly	synonymous	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.70485G>T	p.Gly23495Gly	synonymous	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152140 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00238 AC: 591 AN: 248500 AF XY: 0.00225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.000391

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.000890 AC: 1301 AN: 1461358 Hom.: 17 Cov.: 36 AF XY: 0.000798 AC XY: 580 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0222 AC: 1184 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000648 AC: 72 AN: 1111682

Other (OTH) AF: 0.000746 AC: 45 AN: 60356

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152258 Hom.: 5 Cov.: 32 AF XY: 0.00300 AC XY: 223 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0269 AC: 286 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67990

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.0000680

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.079
DANN	Benign	0.72
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs190149868; hg19: chr2-179440098; COSMIC: COSV104645707;