rs67041405

Variant names:

• chr2-178576659-G-A
• rs67041405
• NM_001267550.2:c.69585C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.69585C>T​(p.Ser23195Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,488 control chromosomes in the GnomAD database, including 222 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 (25 hom., cov: 32)
  • Exomes 𝑓: 0.013 (197 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: -1.02
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-178576659-G-A is Benign according to our data. Variant chr2-178576659-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1710/152084) while in subpopulation NFE AF = 0.0157 (1068/67950). AF 95% confidence interval is 0.0149. There are 25 homozygotes in GnomAd4. There are 896 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.69585C>T	p.Ser23195Ser	synonymous	Exon 325 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.64662C>T	p.Ser21554Ser	synonymous	Exon 275 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.61881C>T	p.Ser20627Ser	synonymous	Exon 274 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.69585C>T	p.Ser23195Ser	synonymous	Exon 325 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.69429C>T	p.Ser23143Ser	synonymous	Exon 323 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.69309C>T	p.Ser23103Ser	synonymous	Exon 323 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1710 AN: 151966 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0118 AC: 2932 AN: 248718 AF XY: 0.0116

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0424

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.00845

GnomAD4 exome AF: 0.0134 AC: 19565 AN: 1461404 Hom.: 197 Cov.: 36 AF XY: 0.0131 AC XY: 9556 AN XY: 726994

African (AFR) AF: 0.00191 AC: 64 AN: 33448

American (AMR) AF: 0.00271 AC: 121 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86246

European-Finnish (FIN) AF: 0.0414 AC: 2212 AN: 53400

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0146 AC: 16235 AN: 1111658

Other (OTH) AF: 0.0113 AC: 684 AN: 60356

GnomAD4 genome AF: 0.0112 AC: 1710 AN: 152084 Hom.: 25 Cov.: 32 AF XY: 0.0121 AC XY: 896 AN XY: 74336

African (AFR) AF: 0.00224 AC: 93 AN: 41520

American (AMR) AF: 0.00412 AC: 63 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.0425 AC: 450 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0157 AC: 1068 AN: 67950

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.0145 Hom.: 44

Bravo AF: 0.00786

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0112

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Cardiomyopathy (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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.14
DANN	Benign	0.80
PhyloP100		-1.0
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs67041405; hg19: chr2-179441386; COSMIC: COSV60087144; COSMIC: COSV60087144;