rs2328878

Variant names:

• chr6-25297457-A-G
• rs2328878
• NM_017640.6:c.138+12548A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017640.6(CARMIL1):​c.138+12548A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 151,990 control chromosomes in the GnomAD database, including 14,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14179 hom., cov: 33)
• Consequence: CARMIL1 NM_017640.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00900

Genes affected

CARMIL1 (HGNC:21581): (capping protein regulator and myosin 1 linker 1) Involved in several processes, including actin filament network formation; plasma membrane bounded cell projection organization; and positive regulation of cellular component organization. Located in several cellular components, including lamellipodium; macropinosome; and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

CMAHP (HGNC:2098): (cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene) Sialic acids are terminal components of the carbohydrate chains of glycoconjugates involved in ligand-receptor, cell-cell, and cell-pathogen interactions. The two most common forms of sialic acid found in mammalian cells are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative, N-glycolylneuraminic acid (Neu5Gc). Studies of sialic acid distribution show that Neu5Gc is not detectable in normal human tissues although it was an abundant sialic acid in other mammals. Neu5Gc is, in actuality, immunogenic in humans. The absense of Neu5Gc in humans is due to a deletion within the human gene CMAH encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase, an enzyme responsible for Neu5Gc biosynthesis. Sequences encoding the mouse, pig, and chimpanzee hydroxylase enzymes were obtained by cDNA cloning and found to be highly homologous. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 6 of the mouse hydroxylase gene, causes a frameshift mutation and premature termination of the polypeptide chain in human. It seems unlikely that the truncated human hydroxylase mRNA encodes for an active enzyme explaining why Neu5Gc is undetectable in normal human tissues. Human genomic DNA also shows evidence of this deletion which does not occur in the genomes of African great apes. Nonetheless, the CMAH gene maps to 6p21.32 in humans and great apes indicating that mutation of the CMAH gene occurred following human divergence from chimpanzees and bonobos. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARMIL1	NM_017640.6	c.138+12548A>G		intron_variant	Intron 2 of 36	ENST00000329474.7	NP_060110.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARMIL1	ENST00000329474.7	c.138+12548A>G		intron_variant	Intron 2 of 36	1	NM_017640.6	ENSP00000331983.6
CARMIL1	ENST00000461945.1	c.-112+12548A>G		intron_variant	Intron 2 of 8	1		ENSP00000489403.1
CARMIL1	ENST00000700669.1	c.138+12548A>G		intron_variant	Intron 2 of 36			ENSP00000515137.1
CMAHP	ENST00000643807.1	n.364+72489T>C		intron_variant	Intron 3 of 15

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63552 AN: 151872 Hom.: 14170 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.417

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.418 AC: 63584 AN: 151990 Hom.: 14179 Cov.: 33 AF XY: 0.423 AC XY: 31413 AN XY: 74288

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.485

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.483

Gnomad4 OTH AF: 0.420

Alfa AF: 0.465 Hom.: 7908

Bravo AF: 0.401

Asia WGS AF: 0.476 AC: 1654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.92
DANN	Benign	0.51

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: rs2328878; hg19: chr6-25297685;