12-22065215-C-T

Position:

• chr12-22065215-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_018686.6(CMAS):​c.1209C>T​(p.Tyr403=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,614,060 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: CMAS NM_018686.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.426

Genes affected

CMAS (HGNC:18290): (cytidine monophosphate N-acetylneuraminic acid synthetase) This gene encodes an enzyme that converts N-acetylneuraminic acid (NeuNAc) to cytidine 5'-monophosphate N-acetylneuraminic acid (CMP-NeuNAc). This process is important in the formation of sialylated glycoprotein and glycolipids. This modification plays a role in cell-cell communications and immune responses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

LOC105369690 (HGNC:):

ST8SIA1 (HGNC:10869): (ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1) Gangliosides are membrane-bound glycosphingolipids containing sialic acid. Ganglioside GD3 is known to be important for cell adhesion and growth of cultured malignant cells. The protein encoded by this gene is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to GM3 to produce gangliosides GD3 and GT3. The encoded protein may be found in the Golgi apparatus and is a member of glycosyltransferase family 29. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-22065215-C-T is Benign according to our data. Variant chr12-22065215-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CMAS	NM_018686.6	c.1209C>T	p.Tyr403=	synonymous_variant	8/8	ENST00000229329.7
LOC105369690	XR_931423.4	n.445+1130G>A		intron_variant, non_coding_transcript_variant
CMAS	NR_135117.2	n.1123C>T		non_coding_transcript_exon_variant	7/7
LOC105369690	XR_931424.4	n.1459+1130G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMAS	ENST00000229329.7	c.1209C>T	p.Tyr403=	synonymous_variant	8/8	1	NM_018686.6	P1
CMAS	ENST00000534981.5	c.*245C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	1
ST8SIA1	ENST00000536535.1	n.291+1130G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 430 AN: 152150 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00344 AC: 866 AN: 251420 Hom.: 5 AF XY: 0.00369 AC XY: 502 AN XY: 135888

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00504

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00376 AC: 5493 AN: 1461792 Hom.: 17 Cov.: 30 AF XY: 0.00379 AC XY: 2757 AN XY: 727210

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.000842

Gnomad4 NFE exome AF: 0.00419

Gnomad4 OTH exome AF: 0.00440

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152268 Hom.: 2 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74448

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00462 Hom.: 9

Bravo AF: 0.00298

EpiCase AF: 0.00573

EpiControl AF: 0.00693

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CMAS: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.9
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs146887115; hg19: chr12-22218149; COSMIC: COSV99982598; COSMIC: COSV99982598;