rs189389531

Variant names:

• chr2-178654210-T-C
• rs189389531
• NM_001267550.2:c.38378A>G

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.38378A>G​(p.Lys12793Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,595,486 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (4 hom., cov: 22)
  • Exomes 𝑓: 0.00039 (26 hom.)
• Consequence: TTN NM_001267550.2 missense
• Scores: Splicing: ADA: 0.0009225
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.199
• 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.006262183).
• BP6: Variant 2-178654210-T-C is Benign according to our data. Variant chr2-178654210-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000421 (63/149710) while in subpopulation EAS AF = 0.00995 (51/5124). AF 95% confidence interval is 0.00778. There are 4 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.38378A>G	p.Lys12793Arg	missense	Exon 193 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34523-1669A>G		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31742-1669A>G		intron	N/A	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.38378A>G	p.Lys12793Arg	missense	Exon 193 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.38378A>G	p.Lys12793Arg	missense	Exon 193 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38102A>G	p.Lys12701Arg	missense	Exon 191 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 63 AN: 149600 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00993

Gnomad SAS AF: 0.00136

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.00119 AC: 278 AN: 233132 AF XY: 0.00118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0143

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000392 AC: 567 AN: 1445776 Hom.: 26 Cov.: 32 AF XY: 0.000417 AC XY: 300 AN XY: 719130

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.0000233 AC: 1 AN: 42848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0113 AC: 449 AN: 39666

South Asian (SAS) AF: 0.000825 AC: 69 AN: 83664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110214

Other (OTH) AF: 0.000732 AC: 44 AN: 60090

GnomAD4 genome AF: 0.000421 AC: 63 AN: 149710 Hom.: 4 Cov.: 22 AF XY: 0.000563 AC XY: 41 AN XY: 72836

African (AFR) AF: 0.00 AC: 0 AN: 41072

American (AMR) AF: 0.0000701 AC: 1 AN: 14272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00995 AC: 51 AN: 5124

South Asian (SAS) AF: 0.00136 AC: 6 AN: 4410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10404

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67666

Other (OTH) AF: 0.00191 AC: 4 AN: 2098

Alfa AF: 0.000299 Hom.: 1

Bravo AF: 0.000725

ExAC AF: 0.00113 AC: 133

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.4
DANN	Benign	0.42
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0063	T
PhyloP100		-0.20
Vest4		0.14
MVP		0.72
GERP RS		0.71
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.010		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: rs189389531; hg19: chr2-179518937; COSMIC: COSV107419469; COSMIC: COSV107419469;