20-6006331-C-G

Variant names:

• chr20-6006331-C-G
• rs964454807
• NM_019095.6:c.85C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019095.6(CRLS1):​c.85C>G​(p.Arg29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,352,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: CRLS1 NM_019095.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0920
• Publications: 0 publications found

Genes affected

CRLS1 (HGNC:16148): (cardiolipin synthase 1) This gene encodes a member of the CDP-alcohol phosphatidyltransferase class-I family of proteins. The encoded enzyme catalyzes the synthesis of cardiolipin, a phospholipid component of mitochondrial membranes that is critical for mitochondrial function. [provided by RefSeq, Apr 2016]

ENSG00000286235 (HGNC:):

MCM8-AS1 (HGNC:51230): (MCM8 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059006184).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019095.6. 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
	CRLS1	NM_019095.6	MANE Select	c.85C>G	p.Arg29Gly	missense	Exon 1 of 7	NP_061968.1	Q9UJA2-1
	CRLS1	NM_001323563.2		c.-311C>G		5_prime_UTR	Exon 1 of 7	NP_001310492.1
	CRLS1	NM_001323562.2		c.-28+220C>G		intron	N/A	NP_001310491.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLS1	ENST00000378863.9	TSL:1 MANE Select	c.85C>G	p.Arg29Gly	missense	Exon 1 of 7	ENSP00000368140.4	Q9UJA2-1
	CRLS1	ENST00000452938.5	TSL:1	c.85C>G	p.Arg29Gly	missense	Exon 1 of 6	ENSP00000416770.1	Q6NTG3
	ENSG00000286235	ENST00000652720.1		c.2431-3444C>G		intron	N/A	ENSP00000498784.1	A0A494C100

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151808 Hom.: 0 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: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.33e-7 AC: 1 AN: 1200834 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 586016

African (AFR) AF: 0.00 AC: 0 AN: 24830

American (AMR) AF: 0.00 AC: 0 AN: 18244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19340

East Asian (EAS) AF: 0.0000378 AC: 1 AN: 26440

South Asian (SAS) AF: 0.00 AC: 0 AN: 49534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 982896

Other (OTH) AF: 0.00 AC: 0 AN: 48446

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151808 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74148

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.3
DANN	Benign	0.54
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.092
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.022
Sift	Benign	0.22	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.075
MutPred		0.31		Loss of solvent accessibility (P = 0.0299)
MVP		0.16
MPC		0.15
ClinPred		0.063	T
GERP RS		-0.62
PromoterAI		0.0016	Neutral
Varity_R		0.076
gMVP		0.34
Mutation Taster		=97/3	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: rs964454807; hg19: chr20-5986977;